Aryl or heteroaryl fused imidazole compounds as anti-inflammatory and analgesic agents

ABSTRACT

This invention provides a compound of the formula (I):  
                 
 
     or the pharmaceutically acceptable salts thereof, wherein Y 1 , Y 2 , Y 3  and Y 4  are independently selected from N, CH, etc.; R 1  is H, C 1-8  alkyl, etc.; Q 1  is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, etc.; A is a 5-6 membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, etc.; B is C 1-6  alkylene optionally substituted with an oxo group, etc.; W is NH, O, etc.; R 2  is H, C 1-4  alkyl, etc.; Z is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, etc.; L is halo, C 1-4  alkyl, etc.; m is 0, 1 or 2; R 3  and R 4  are independently selected from H and C 1-4  alkyl; R 5  is H, C 1-4  alkyl, etc.; Q 2  is a 5-12 membered monocyclic or bicyclic aromatic ring or tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, etc. These compounds are useful for the treatment of medical conditions mediated by prostaglamndin such as pain, fever or inflammation, etc. This invention also provides a pharmaceutical composition comprising the above compound.

[0001] This application is a Divisional of U.S. Ser. No. 09/977,621filed Oct. 15, 2001, which claimed priority to U.S. Ser. No. 60/421,825filed Oct. 19, 2000.

TECHNICAL FIELD

[0002] This invention relates to aryl or heteroaryl fused imidazolecompounds, or their pharmaceutically acceptable salts, pharmaceuticalcompositions containing them, and their medical uses. The compounds ofthis invention have activity as prostaglandin E₂ receptor antagonists,and these are useful in the treatment or alleviation of pain andinflammation and other inflammation-associated disorders, such asarthritis. treating or preventing disorders or medical conditionsselected from pain, inflammatory diseases and the like.

BACKGROUND ART

[0003] Prostaglandins are mediators of pain, fever and other symptomsassociated with inflammation. Especially prostaglandin E₂ (PGE₂) is thepredominant eicosanoid detected in inflammation conditions. In addition,it is also involved in various physiological and/or pathologicalconditions and such as hyperalgesia, uterine contraction, digestiveperistalsis, awakeness, suppression of gastric acidsecretion, bloodpressure, platelet function, bone metabolism, angiogenesis or the like.

[0004] Four PGE₂ receptor subtypes (EP₁, EP₂, EP₃ and EP₄) displayingdifferent pharmacological properties have been cloned. EP₄ subtype, aGs-coupled receptor stimulates cAMP production, and is distributed in awide variety of tissue suggesting major role in PGE₂-mediated biologicalevents.

[0005] WO99/47497 discloses carboxylic acids and acylsulfonamidescompounds as prostaglandin-receptor antagonists.

BRIEF DISCLOSURE OF THE INVENTION

[0006] The present invention provides a compound of the followingformula:

[0007] or the pharmaceutically acceptable salts thereof, wherein

[0008] Y¹, Y², Y³ and Y⁴ are independently selected from N, CH or C(L);

[0009] R¹ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkyl,C₁₋₈ alkoxy, halo-substituted C₁₋₈ alkoxy, C₁₋₈ alkyl-S(O)m-, Q¹—,pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- ordi-(C₁₋₈ alkyl)amino, C₁₋₄alkyl-C(═O)—N(R³)— or C₁₋₄alkyl-S(O)m-N(R³)—,wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl are optionallysubstituted with halo, C₁₋₃ alkyl, hydroxy, oxo, C₁₋₄ alkoxy-, C₁₋₄alkyl-S(O)m-, C₃₋₇ cycloalkyl-, cyano, indanyl,1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl,oxopyrrolidinyl, oxopiperidyl, Q¹—, Q¹—C(═O)—, Q¹—O—, Q¹—S(O)m-,Q¹—C₁₋₄alkyl-O—, Q¹—C₁₋₄alkyl-S(O)m-, Q¹—C₁₋₄alkyl-C(O)—N(R³)—,Q¹—C₁₋₄alkyl-N(R³)— or C₁₋₄alkyl-C(O)—N(R³)—;

[0010] Q¹ is a 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 4 heteroatoms selected from O, N and S, andis optionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄alkyl)amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,C₁₋₄alkylC(═O)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, R³N(R⁴)C(═O)—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— or NH₂(HN═)C—;

[0011] A is a 5-6 membered monocyclic aromatic ring optionallycontaining up to 3 heteroatoms selected from O, N and S, wherein said5-6 membered monocyclic aromatic ring is optionally substituted with upto 3 substituents selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy,C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino, cyano,HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,acetyl, R³N(R⁴)C(═O)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— and NH₂(HN═)C—;

[0012] B is halo-substituted C₁₋₆ alkylene, C₃₋₇ cycloalkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, —O—C₁₋₅ alkylene, C₁₋₂ alkylene-O—C₁₋₂alkylene or C₁₋₆ alkylene optionally substituted with an oxo group orC₁₋₃ alkyl;

[0013] W is NH, N—C₁₋₄ alkyl, O, S, N—OR⁵ or a covalent bond;

[0014] R² is H, C₁₋₄ alkyl, OH or C₁₋₄ alkoxy;

[0015] Z is a 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 3 heteroatoms selected from O, N and S,wherein said 5-12 membered monocyclic or bicyclic aromatic ring isoptionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, hydroxy, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, nitro, amino, mono- ordi-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O)—, R³C(═O)N(R⁴)—, HO(O═)C—,C₁₋₄alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl, NH₂(HN═)C—,Q²-S(O)m-, Q²—O—, Q²—N(R³)— or Q²—;

[0016] L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, nitro, amino,mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O)—,HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl,R³C(═O)N(R⁴)—, NH₂(HN═)C—, R³N(R⁴)C(═O)—, R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—,Q²—O—, Q²—C₁₋₄alkyl-O—, or two adjacent L groups are optionally joinedtogether to form an alkylene chain having 3 or 4 members in which one ortwo (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;

[0017] m is 0, 1 or 2;

[0018] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl;

[0019] R⁵ is H, C₁₋₄ alkyl, C₁₋₄ alkyl-(O═)C— or C₁₋₄ alkyl-O—(O═)C—;and

[0020] Q² is a 5-12 membered monocyclic or bicyclic aromatic ring, or a5-12 membered tricyclic ring optionally containing up to 3 heteroatomsselected from O, N and S, wherein said 5-12 membered monocyclic orbicyclic aromatic ring is optionally substituted with halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, nitro, amino,mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkyl-(O═)C—,R³(R⁴)C(═O)N—, HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino,C₃₋₇ cycloalkyl, C₁₋₄ alkyl-C(═O)NH— or NH₂(HN═)C—.

[0021] The aryl or heteroaryl fused imidazole compounds of thisinvention have an antagonistic action towards prostaglandin and are thususeful in therapeutics, particularly for the treatment of a disorder orcondition selected from the group consisting of pain, fever orinflammation associated with rheumatic fever, influenza or other viralinfections, common cold, low back and neck pain, skeletal pain,post-partum pain, dysmenorrhea, headache, migraine, toothache, sprainsand strains, myositis, neuralgia, fibromyalgia, synovitis, arthritis,including rheumatoid arthritis, degenerative joint diseases(osteoarthritis), gout and ankylosing sspondylitis, bursitits, burnsincluding radiation and corrosive chemical injuries, sunburns, painfollowing surgical and dental procedures or bone fracture, immune andautoimmune diseases such as systemic lupus erythematosus; AlDS(acquiredimmuno deficiency syndrome), gastrointestinal cancers such as coloncancer; cellular neoplastic transformations or metastic tumor growth;Diabetic retinopathy, tumor angiogenesis; prostanoid-induced smoothmuscle contraction associated with dysmenorrhea, premature labor,allergic rhinitis, atopic dermatitis, asthma or eosinophil relateddisorders, Hyperimmunoglobulinaemia, Castleman's disease, myeloma;Alzheimer's disease, sleep disorders, endocrine disturbance; glaucoma;bone loss; osteoporosis; promotion of bone formation; Paget's disease:cytoprotection in peptic ulcers, gastritis, regional enteritis,ulcerative colitis, diverticulitis or other gastrointestinal lesions; GIbleeding and patients undergoing chemotherapy; coagulation disordersselected from hypoprothrombinemia, haemophilia and other bleedingproblems; kidney disease; thrombosis; occlusive vascular disease;presurgery; and anti-coagulation, or the like in mammalian, especiallyhumans.

[0022] The present invention provides a pharmaceutical composition forthe treatment of a disorder or condition mediated by prostaglandin, in amammalian including a human, which comprises administering to saidsubject a therapeutically effective amount of a compound of formula (I).

[0023] Further, the present invention also provides a pharmaceuticalcomposition for the treatment of a disorder or condition selected fromthe group consisting of pain, fever or inflammation associated withrheumatic fever, influenza or other viral infections, common cold, lowback and neck pain, skeletal pain, post-partum pain, dysmenorrhea,headache, migraine, toothache, sprains and strains, myositis, neuralgia,fibromyalgia, synovitis, arthritis, including rheumatoid arthritis,degenerative joint diseases (osteoarthritis), gout and ankylosingsspondylitis, bursitits, burns including radiation and corrosivechemical injuries, sunburns, pain following surgical and dentalprocedures, bone fracture, immune and autoimmune diseases such assystemic lupus erythematosus; AIDS(acquired immuno deficiency syndrome),gastrointestinal cancers such as colon cancer; cellular neoplastictransformations or metastic tumor growth; Diabetic retinopathy, tumorangiogenesis; prostanoid-induced smooth muscle contraction associatedwith dysmenorrhea, premature labor, allergic rhinitis, atopicdermatitis, asthma or eosinophil related disorders,Hyperimmunoglobulinaemia, Castleman's disease, myeloma; Alzheimer'sdisease, sleep disorders, endocrine disturbance; glaucoma; bone loss;osteoporosis; promotion of bone formation; Paget's disease:cytoprotection in peptic ulcers, gastritis, regional enteritis,ulcerative colitis, diverticulitis or other gastrointestinal lesions; GIbleeding and patients undergoing chemotherapy; coagulation disordersselected from hypoprothrombinemia, haemophilia and other bleedingproblems; kidney disease; thrombosis; occlusive vascular disease;presurgery; and anti-coagulation, or the like, which comprises atherapeutically effective amount of the aryl or heteroaryl fusedimidazole compound of formula (I) or its pharmaceutically acceptablesalt together with a pharmaceutically acceptable carrier.

[0024] Also, the present invention provides a method for the treatmentof a disorder or condition mediated by prostaglandin, in a mammalianincluding a human, which comprises administering to said subject atherapeutically effective amount of a compound of formula (I).

[0025] Further, the present invention provides a method for thetreatment of pain, fever or inflammation associated with rheumaticfever, influenza or other viral infections, common cold, low back andneck pain, skeletal pain, post-partum pain, dysmenorrhea, headache,migraine, toothache, sprains and strains, myositis, neuralgia,fibromyalgia, synovitis, arthritis, including rheumatoid arthritis,degenerative joint diseases (osteoarthritis), gout and ankylosingsspondylitis, bursitits, burns including radiation and corrosivechemical injuries, sunburns, pain following surgical and dentalprocedures, bone fracture, immune and autoimmune diseases such assystemic lupus erythematosus; AIDS, gastrointestinal cancers such ascolon cancer ;cellular neoplastic transformations or metastic tumorgrowth; Diabetic retinopathy, tumor angiogenesis; prostanoid-inducedsmooth muscle contraction associated with dysmenorrhea, premature labor,allergic rhinitis, atopic dermatitis, asthma or eosinophil relateddisorders, Hyperimmunoglobulinaemia, Castleman's disease, myeloma;Alzheimer's disease, sleep disorders, endocrine disturbance; glaucoma;bone loss; osteoporosis; promotion of bone formation; Paget's disease:cytoprotection in peptic ulcers, gastritis, regional enteritis,ulcerative colitis, diverticulitis or other gastrointestinal lesions; GIbleeding and patients undergoing chemotherapy; coagulation disordersselected from hypoprothrombinemia, haemophilia and other bleedingproblems; kidney disease; thrombosis; occlusive vascular disease;presurgery; and anti-coagulation or the like, in a mammalian subject,which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I).

[0026] Also, the present invention provides a pharmaceutical formulationcomprising a compound of formula (I), a pharmaceutically acceptablecarrier and, optionally, one or more other pharmacologically activeingredients.

[0027] Also, the present invention provides a pharmaceutical formulationcomprising a compound of formula (I), a pharmaceutically acceptablecarrier and, optionally, one or more other pharmacologically activeingredients selected from a COX-2 selective, COX-1 selective ornon-selective NSAIDs(nonsteroidal anti-inflammatory drugs), opioids,anticonvulsants, antidepressants, local anesthetics, disease-modifyinganti-rheumatoid drugs, or steroids.

[0028] Also, the present invention provides a compound of the followingformula:

[0029] or salts thereof

[0030] wherein Y¹, Y², Y³ and Y⁴ are independently selected from N, CHor C(L);

[0031] R¹ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkyl,C₁₋₈ alkoxy, halo-substituted C₁₋₈ alkoxy, C₁₋₈ alkyl-S(O)m-, Q¹—,amino, mono- or di-(C₁₋₈ alkyl)amino, C₁₋₄alkyl-C(═O)—N(R³)— orC₁₋₄alkyl-S(O)m-N(R³)—, wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈alkynyl are optionally substituted with halo, C₁₋₃ alkyl, C₁₋₄ alkoxy-,C₁₋₄ alkyl-S(O)m-, C₃₋₇ cycloalkyl-, cyano, indanyl,1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, Q¹—, Q¹—C(═O)—, Q¹—O—,Q¹—S(O)m-, Q¹—C₁₋₄alkyl—O—, Q¹—C₁₋₄alkyl-S(O)m-,Q¹—C₁₋₄alkyl-C(O)—N(R³)— or Q¹—C₁₋₄alkyl-N(R³)—;

[0032] Q¹ is a 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 4 heteroatoms selected from O, N and S, andis optionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄alkyl)amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,C₁₋₄alkylC(═O)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, R³N(R⁴)C(═O)—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— or NH₂(HN═)C—;

[0033] A is a benzene ring optionally substituted with up to 3substituents or pyridine ring optionally substituted with up to 3substituents, wherein said substituents selected from halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino,cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl,aminosulfonyl, acetyl, R³N(R⁴)C(═O)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— and NH₂(HN═)C—;

[0034] B is C₂₋₆ alkylene, C₃₋₇ cycloalkylene, C₂₋₆ alkenylene, or C₂₋₆alkynylene optionally substituted with C₁₋₃ alkyl;

[0035] W is NH or O;

[0036] P is H, a protecting group, or Q³—OC(═O)—;

[0037] Q³ is a 6-10 membered monocyclic or bicyclic aromatic ringoptionally substituted with halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, cyano, C₁₋₄ alkylsulfonyl, C₁₋₄alkylC(═O)—, HO(O═)C—,or C₁₋₄alkyl-O(O═)C—;

[0038] L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, nitro, amino,mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O)—,HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl,R³C(═O)N(R⁴)—, NH₂(HN═)C—, R³N(R⁴)C(═O)— or R³N(R⁴)S(O)m-, or twoadjacent L groups are optionally joined together to form an alkylenechain having 3 or 4 members in which one or two (non-adjacent) carbonatoms are optionally replaced by oxygen atoms;

[0039] m is 0, 1 or 2; and

[0040] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl.

[0041] Also, the present invention provides a compound of the followingformula:

[0042] or salts thereof

[0043] wherein Y¹, Y², Y³ and Y⁴ are independently selected from N, CHor C(L);

[0044] R¹ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkyl,C₁₋₈ alkoxy, halo-substituted C₁₋₈ alkoxy, C₁₋₈ alkyl-S(O)m-, Q¹—,amino, mono- or di-(C₁₋₈ alkyl)amino, C₁₋₄alkyl-C(═O)—N(R³)— orC₁₋₄alkyl-S(O)m-N(R³)—, wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈alkynyl are optionally substituted with halo, C₁₋₃ alkyl, C₁₋₄ alkoxy-,C₁₋₄ alkyl-S(O)m-, C₃₋₇ cycloalkyl-, cyano, indanyl,1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, Q¹—, Q¹—C(═O)—Q¹—O—,Q¹—S(O)m-, Q¹—C₁₋₄alkyl—O—, Q¹—C₁₋₄alkyl-S(O)m-,Q¹—C₁₋₄alkyl-C(O)—N(R³)— or Q¹—C₁₋₄alkyl-N(R³)—;

[0045] Q¹ is a 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 4 heteroatoms selected from O, N and S, andis optionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄alkyl)amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,C₁₋₄alkylC(═O)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, R³N(R⁴)C(═O)—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— or NH₂(HN═)C—;

[0046] A is a benzene ring optionally substituted with up to 3substituents or pyridine ring optionally substituted with up to 3substituents, wherein said substituents selected from halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino,cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl,aminosulfonyl, acetyl, R³N(R⁴)C(═O)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— and NH₂(HN═)C—;

[0047] B is C₂₋₆ alkylene, C₃₋₇ cycloalkylene, C₂₋₆ alkenylene, or C₂₋₆alkynylene optionally substituted with C₁₋₃ alkyl;

[0048] W is NH or O;

[0049] P is H, a protecting group, or Z—S(O)₂—N(R²)—C(═O)—;

[0050] Z is a 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 3 heteroatoms selected from O, N and S,wherein said 5-12 membered monocyclic or bicyclic aromatic ring isoptionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, hydroxy, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, nitro, amino, mono- ordi-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O)—, R³C(═O)N(R⁴)—, HO(O═)C—,C₁₋₄alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl, NH₂(HN═)C—,Q²—S(O)m-, Q²—O—, Q²—N(R³)— or Q²—;

[0051] L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, nitro, amino,mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O) —,HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl,R³C(═O)N(R⁴)—, NH₂(HN═)C—, R³N(R⁴)C(═O)— or R³N(R⁴)S(O)m-, or twoadjacent L groups are optionally joined together to form an alkylenechain having 3 or 4 members in which one or two (non-adjacent) carbonatoms are optionally replaced by oxygen atoms;

[0052] m is 0, 1 or 2; and

[0053] R², R³, and R⁴ are independently selected from H and C₁₋₄ alkyl.

DETAILED DESCRIPTION OF THE INVENTION

[0054] The term “alkyl”, as used herein, means a straight or branchedsaturated monovalent hydrocarbon radical including, but not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, neopentyl and the like.

[0055] The term “alkenyl”, as used herein, means a hydrocarbon radicalhaving at least one double bond including, but not limited to, ethenyl,propenyl, 1-butenyl, 2-butenyl and the like.

[0056] The term “alkynyl”, as used herein, means a hydrocarbon radicalhaving at least one triple bond including, but not limited to, ethynyl,propynyl, 1-butynyl, 2-butynyl and the like.

[0057] The term “halo”, as used herein, refers to F, Cl, Br or I,preferably F or Cl.

[0058] The term “cycloalkyl”, as used herein, means a saturatedcarbocyclic radical including, but not limited to, cyclopropyl,cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyland the like.

[0059] The term “alkoxy”, as used herein, means an O-alkyl group wherein“alkyl” is defined above.

[0060] The term “monocyclic aromatic ring”, as used herein, means amonocyclic aromatic carbocyclic or heterocyclic ring (and containing 0-4heteroatoms selected from O, N and S) including, but not limited to,phenyl, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl,imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl,pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyland the like.

[0061] The term “bicyclic aromatic ring”, as used herein, means amonocyclic or bicyclic aromatic carbocyclic or heterocyclic ring (andcontaining 0-4 heteroatoms selected from O, N and S) including, but notlimited to, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl,indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl,benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl quinoxalinyl and the like.

[0062] The term “alkylene”, as used herein, means saturated hydrocarbon(straight chain or branched) wherein a hydrogen atom is removed fromeach of the terminal carbons such as methylene, ethylene, propylene,butylene, pentylene, hexylene and the like.

[0063] The term “cycloalkylene”, as used herein, means divalentcycloalkyl groups including, but not limited to, cyclopropylene,cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene and thelike.

[0064] The term “alkenylene”, as used herein, means a straight orbranched hydrocarbon chain spacer radical having at least one doublebond including, but not limited to, —CH═CH—, —CH═CHCH—, —CH═CHCH(CH₃)—,and the like.

[0065] The term “alkynylene”, as used herein, means a straight orbranched hydrocarbon chain spacer radical having at least one triplebond including, but not limited to,—C≡C—, —C—C≡CCH₂—, —C≡CCH(CH₃)—, andthe like.

[0066] The term “tricyclic ring”, as used herein, means a saturatedcarbocyclic radical including, but not limited to, adamantyl,tricyclo[5.2.1.0^(2,6)]decane, and the like.

[0067] The term “two adjacent L groups are optionally joined together toform an alkylene chain having 3 or 4 members in which one or two(non-adjacent) carbon atoms are optionally replaced by oxygen atoms”, asused herein, means, but not limited to, —O—CH₂—O—, —CH₂—O—CH₂—,—O—CH₂CH₂—, —CH₂CH₂—O—, —O—CH₂CH₂—O—, —CH₂CH₂CH₂—O—, —O—CH₂CH₂CH₂—,—CH₂—O—CH₂CH₂—, —CH₂CH₂—O—CH₂—, and the like.

[0068] The term “aryl”, as used herein, means aromatic radicalsincluding, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, biphenyl and the like.

[0069] The term “protecting group”, as used herein, means a hydroxy oramino protecting group which is selected from typical hydroxy or aminoprotecting groups described in Protective Groups in Organic Synthesisedited by T. W. Greene et al. (John Wiley & Sons, 1991);

[0070] The term “treating”, as used herein, refers to reversing,alleviating, inhibiting the progress of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treatment” as used herein refers to theact of treating, as “treating” is defined immediately above.

[0071] In the compounds of formula (I),

[0072] Y¹, Y², Y³, and Y⁴ are preferably independently selected from N,CH and C(L);

[0073] L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, mono- or di-(C₁₋₄ alkyl)amino, halo-substituted C₁₋₄ alkoxy,cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl,aminosulfonyl, C₁₋₄ alkylC(═O)—, HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)—, R³N(R⁴)C(═O)—,R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—, Q²—O—, Q²—C₁₋₄alkyl-O—, or two adjacent Lgroups are optionally joined together to form an alkylene chain having 3or 4 members in which one or two (non-adjacent) carbon atoms areoptionally replaced by oxygen atoms;

[0074] m is 0or 2;

[0075] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0076] Q² is a 5-12 membered monocyclic or bicyclic aromatic ring, or a8-12 membered tricyclic ring optionally containing up to 3 heteroatomsselected from O, N and S, wherein said 5-12 membered monocyclic orbicyclic aromatic ring is optionally substituted with halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, mono- or di-(C₁₋₄alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, C₁₋₄ alkyl-(O═)C—, R³(R⁴)C(═O)N—,HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkylor C₁₋₄ alkyl-C(═O)NH—, more preferably Y¹, Y², Y³, and Y⁴ areindependently selected from N, CH and C(L);

[0077] L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, mono- or di-(C₁₋₄ alkyl)amino, halo-substituted C₁₋₄ alkoxy,cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O)—, HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇cycloalkyl, R³C(═O)N(R⁴)—, R³N(R⁴)C(═O)—,

[0078] R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—, Q²—O—, Q²—C₁₋₄alkyl-O—, or twoadjacent L groups are optionally joined together to form an alkylenechain having 3 or 4 members in which one or two (non-adjacent) carbonatoms are optionally replaced by oxygen atoms;

[0079] m is 0 or 2;

[0080] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0081] Q² is a 5 or 6 membered monocyclic aromatic ring, or a 8-12membered tricyclic ring containing up to 3 heteroatoms selected from Nand S, wherein said 5 or 6 membered monocyclic aromatic ring isoptionally substituted with halo, more preferably Y¹, Y², Y³, and Y⁴ areindependently selected from N, CH and C(L);

[0082] m is 0 or 2;

[0083] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0084] Q² is 5 or 6 membered monocyclic aromatic ring or a 8-12 memberedtricyclic ring optionally containing 1 sulfur atom wherein said 5 or 6membered monocyclic aromatic ring is optionally substituted with halo,more preferably Y¹, Y², Y³, and Y⁴ are independently selected from N, CHand C(L);

[0085] L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, cyano, HO—C₁₋₄ alkyl, acetyl,R³N(R⁴)C(═O)—, R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—, Q²—O—, Q²—C₁₋₄alkyl-O—, ortwo adjacent L groups are joined together to form a methylenedioxygroup;

[0086] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0087] Q² is 5 or 6 membered monocyclic aromatic ring system, morepreferably Y¹, Y², Y³, and Y⁴ are independently selected from N, CH andC—L;

[0088] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano,acetyl, —C(═O)NH₂, trifuluoromethyloxy, methanesulfonyl, or1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined togetherto form a methylenedioxy group, more preferably Y¹, Y², Y³ and Y⁴ areselected from the group consisting of

[0089] a) Y¹ and Y³ are C(L), Y² is CH and Y⁴ is N;

[0090] b) Y¹ is CH, Y² and Y³ are C(L) and Y⁴ is N;

[0091] c) Y¹, Y² and Y³ are C(L) and Y⁴ is N;

[0092] d) Y¹ and Y³ are C(L), Y² is N and Y⁴ is CH;

[0093] e) Y¹ is C(L) and Y², Y³ and Y⁴ are CH;

[0094] f) Y¹, Y³ and Y⁴ are CH, and Y² is C(L);

[0095] g) Y¹, Y² and Y³ are CH, and Y⁴ is C(L);

[0096] h) Y¹ and Y² are C(L), and Y³ and Y⁴ are CH;

[0097] i) Y¹ and Y³ are C(L), and Y² and Y⁴ are CH;

[0098] j) Y¹ and Y⁴ are CH, and Y² and Y³ are C(L);

[0099] k) Y¹ and Y² are CH, Y³ is C(L) and Y⁴ is N;

[0100] l) Y¹ and Y³ are CH, Y² is C(L) and Y⁴ is N;

[0101] m) Y¹, Y², Y³ and Y⁴ are CH;

[0102] n) Y¹ and Y² are C(L), Y³ is CH and Y⁴ is N;

[0103] o) Y¹, Y² and Y⁴ are CH, and Y³ is C(L);

[0104] p) Y¹ and Y² are C(L), Y³ is N and Y⁴ is CH;

[0105] q) Y¹ and Y³ are C(L), and Y² and Y⁴ are N;

[0106] r) Y¹ is C(L), Y² and Y³ are CH, and Y⁴ is N;

[0107] s) Y² is C(L), Y¹ and Y³ are CH, and Y⁴ is N; and

[0108] t) Y¹, Y² and Y³ are C(L), and Y⁴ is CH

[0109] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano,acetyl, —C(═O)NH₂, trifuluoromethyloxy, methanesulfonyl, or1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined togetherto form a methylenedioxy group, most preferably Y¹, Y², Y³ and Y⁴ areselected from the group consisting of

[0110] a) Y¹ and Y³ are C(L), Y² is CH and Y⁴ is N;

[0111] b) Y¹ is CH, Y² and Y³ are C(L) and Y⁴ is N;

[0112] c) Y¹, Y² and Y³ are C(L) and Y⁴ is N;

[0113] d) Y¹ and Y³ are C(L), Y² is N and Y⁴ is CH;

[0114] e) Y¹ is C(L) and Y², Y³ and Y⁴ are CH;

[0115] f) Y¹, Y³ and Y⁴ are CH, and Y² is C(L);

[0116] g) Y¹, Y² and Y³ are CH, and Y⁴ is C(L);

[0117] h) Y¹ and Y² are C(L), and Y³ and Y⁴ are CH;

[0118] i) Y¹ and Y³ are C(L), and Y² and Y⁴ are CH;

[0119] j) Y¹ and Y⁴ are CH, and Y² and Y³ are C(L); and

[0120] k) Y¹, Y² and Y³ are C(L), and Y⁴ is CH

[0121] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano,acetyl, —C(═O)NH₂, trifuluoromethyloxy, methanesulfonyl, or1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined togetherto form a methylenedioxy group.

[0122] In the compounds of formula (I),

[0123] R¹ is preferably H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₇cycloalkyl, C₁₋₈ alkoxy, halo-substituted C₁₋₈ alkoxy, C₁₋₈alkyl-S(O)m-, Q¹—, pyrrolidinyl, piperidyl, oxopyrrolidinyl,oxopiperidyl, amino, mono- or di-(C₁₋₈ alkyl)amino,C₁₋₄alkyl-C(═O)—N(R³)— or C₁₋₄alkyl-S(O)m-N(R³)—, wherein said C₁₋₈alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl are optionally substituted withhalo, C₁₋₃ alkyl, hydroxy, oxo, C₁₋₄ alkoxy-, C₁₋₄ alkyl-S(O)m-, C₃₋₇cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl,1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl,oxopiperidyl, Q¹—, Q¹—C(═O)—, Q¹—O—, Q¹—S(O)m-, Q¹—C₁₋₄ alkyl-O—,Q¹—C₁₋₄ alkyl-S(O)m-, Q¹—C₁₋₄alkyl-C(O)—N(R³)—, Q¹—C₁₋₄alkyl-N(R³)— orC₁₋₄alkyl-C(O)—N(R³)—;

[0124] Q¹ is a 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 4 heteroatoms selected from O, N and S, andis optionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O)—, HO(O═)C—, C₁₋₄ alkyl-O(O)C—, R³N(R⁴)C(═O)—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— or NH₂(HN═)C—;

[0125] m is 0 or 2; and

[0126] R³ is H or C₁₋₄ alkyl, more preferably R¹ is H, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkyl, Q¹—, pyrrolidinyl, piperidyl,oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C₁₋₈ alkyl)amino,wherein said C₁₋₈ alkyl is optionally substituted with halo, C¹⁻³ alkyl,hydroxy, oxo, C₁₋₄ alkoxy-, C₁₋₄ alkyl-S(O)m-, C₃₋₇ cycloalkyl-, cyano,indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q¹—,Q¹—C(O)—, Q¹—O—, Q¹—S— or Q¹—C₁₋₄ alkyl-O—, or C₁₋₄alkyl-C(O)—N(R³)—;

[0127] Q¹ is a 5-12 membered monocyclic aromatic ring optionallycontaining up to 4 heteroatoms selected from N and S, and is optionallysubstituted with halo, C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl and C₁₋₄alkylC(═O)—; and

[0128] m is 0 or 2, more preferably R¹ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₇ cycloalkyl, Q¹—, or mono- or di-(C₁₋₈ alkyl)aminowherein said C₁₋₈ alkyl is optionally substituted with halo, C₁₋₃ alkyl,hydroxy, oxo, C₁₋₄ alkoxy-, C₁₋₄ alkyl-S(O)m-, C₃₋₇ cycloalkyl-, cyano,indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q¹—,Q¹—C(═O)—, Q¹—O—, Q¹—S—, Q¹—C₁₋₄ alkyl-O—, or C₁₋₄alkyl-C(O)—N(H)—;

[0129] Q¹ is a 5 or 6 membered monocyclic aromatic ring optionallycontaining up to 4 heteroatoms selected from N and S; and

[0130] m is 0 or 2, more preferably R¹ is C₁₋₅ alkyl, C₃₋₇ cycloalkyl,or Q¹—, mono- or di-(C₁₋₈ alkyl)amino wherein said C₁₋₅ alkyl isoptionally substituted with C₁₋₃ alkyl, hydroxy, oxo, pyrrolidinyl,piperidyl, oxopyrrolidinyl, oxopiperidyl, Q¹—, or C₁₋₄alkyl-C(O)—N(H)—;and

[0131] Q¹ is 5-12 membered monocyclic aromatic ring system optionallycontaining up to 2 heteroatoms selected from N and S, more preferably R¹is C₁₋₅ alkyl, mono- or di-(C₁₋₈ alkyl)amino, pyrrolidinyl, or pyridyloptionally substituted with C₁₋₃ alkyl, hydroxy, oxo, 5 or 6 memberedmonocyclic aromatic ring, wherein said 5 or 6 membered monocyclicaromatic ring is containing 1 or 2 heteroatoms selected from N and S, orC₁₋₄alkyl-C(O)—N(H)—, most preferably R¹ is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl methylamino,dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl.

[0132] In the compounds of formula (I),

[0133] R² is preferably H or C₁₋₄ alkyl, most preferably H.

[0134] In the compounds of formula (I),

[0135] A is preferably a 5-6 membered monocyclic aromatic ringoptionally containing up to 2 heteroatoms selected from O, N, and S,wherein said 5-6 membered m onocyclic aromatic ring is optionallysubstituted with up to 2 substituents selecte d from halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy and halo-substitutedC₁₋₄ alkoxy, more preferably 5-6 membered monocyclic aromatic ringoptionally substituted with halo, C₁₋₄ alkyl or C₁₋₄ alkoxy, moreprefera bly 5-6 membered monocyclic aromatic ring system optionallysubstituted with h alo or C₁₋₄ alkyl, more preferably 5-6 memberedmonocyclic aromatic ring syst em, most preferably phenyl or pyridyl.

[0136] In the compounds of formnula (I),

[0137] B is preferably C₃₋₇ cycloalkylene or C₁₋₆ alkylene optionallysubstituted with an oxo group or C₁₋₃ alkyl, more preferably C₁₋₃alkylene optionally substituted with C₁₋₃ alkyl, more preferably C₁₋₂alkylene optionally substituted with methyl, most preferably ethylene orpropylene.

[0138] In the compounds of formula (I),

[0139] W is preferably NH, N—C₁₋₄ alkyl, O or N—OH, more preferably NH,N—C₁₋₂ alkyl or O, most preferably NH, N—CH₃ or O.

[0140] In the compounds of formula (I),

[0141] Z is preferably a 5-12 membered monocyclic or bicyclic aromaticring optionally containing up to 3 heteroatoms selected from, N, O, andS, wherein said 5-12 membered monocyclic or bicyclic aromatic ring isoptionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, C₁₋₄ alkenyl, hydroxy, C₁₋₄ alkoxy, nitro, amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄ alkylC(═O)—,R³C(═O)N(R⁴)—, HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino,C₁₋₄ alkyl-C(═O)NH—, Q²—S(O)m-, Q²—O—, Q²—N(R³)— or Q²—;

[0142] m is 0 or 2;

[0143] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0144] Q² is a 5-12 membered monocyclic or bicyclic aromatic ring, or a8-12 membered tricyclic ring optionally containing up to 3 heteroatomsselected from O, N and S, wherein said 5-12 membered monocyclic orbicyclic aromatic ring is optionally substituted with halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, mono- or di-(C₁₋₄alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, C₁₋₄ alkyl-(O═)C—, R³(R⁴)C(═O)N—,HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkylor C₁₋₄ alkyl-C(═O)NH—, more preferably Z is 5-12 membered monocyclic orbicyclic aromatic ring optionally containing up to 3 heteroatomsselected from, N and S, wherein said 5-12 membered monocyclic orbicyclic aromatic ring is optionally substituted with halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkoxy, nitro, amino,cyano, R³C(═O)N(R⁴)—, C₁₋₄ alkyl-O(O═)C—, Q²—S(O)m-, Q²—O—, Q²—N(R³)— orQ²—;

[0145] m is 0 or 2;

[0146] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0147] Q² is a 5 or 6 membered monocyclic aromatic ring, or a 8-12membered tricyclic ring containing up to 3 heteroatoms selected from Nand S, wherein said 5 or 6 membered monocyclic aromatic ring isoptionally substituted with halo, more preferably Z is 5-12 memberedmonocyclic or bicyclic aromatic ring optionally containing up to 3heteroatoms selected from N and S, wherein said 5-12 membered monocyclicor bicyclic aromatic ring is optionally substituted with halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkoxy, nitro,amino, cyano, R³C(═O)N(R⁴)—, C₁₋₄ alkyl-O(O═)C—, Q²—S(O)m-, Q²—O—,Q²—N(R³)— or Q²—;

[0148] m is 0 or 2;

[0149] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0150] Q² is 5 or 6 membered monocyclic aromatic ring or a 8-12 memberedtricyclic ring optionally containing 1 sulfur atom wherein said 5 or 6membered monocyclic aromatic ring is optionally substituted with halo,more preferably Z is 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 3 heteroatoms selected from N and S, whereinsaid 5-12 membered monocyclic aromatic ring is optionally substitutedwith halo, C₁₋₄ alkyl, nitro, R³C(═O)N(R⁴)— or Q²—;

[0151] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0152] Q² is 5 or 6 membered monocyclic aromatic ring system, morepreferably Z is 5-10 membered monocyclic or bicyclic aromatic ringoptionally containing up to 3 heteroatoms selected from N and S, whereinsaid 5-10 membered monocyclic aromatic ring is optionally substitutedwith chloro, bromo, methyl, nitro, CH₃C(═O)NH—, tBuC(═O)NH—or phenyl,most preferably Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl,thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl,thiadiazolyl and thienyl being optionally substituted with one to threesubstituents independently selected from chloro, bromo, methyl,acetylamino, pivaloylamino, nitro and phenyl.

[0153] A preferred group of compounds of the present invention includescompounds of formula (I) wherein

[0154] Y¹, Y², Y³, and Y⁴ are independently selected from N, CH andC(L);

[0155] R¹ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkyl,C₁₋₈ alkoxy, halo-substituted C₁₋₈ alkoxy, C₁₋₈ alkyl-S(O)m-, Q¹—,pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- ordi-(C₁₋₈ alkyl)amino, C₁₋₄alkyl-C(═O)—N(R³)— or C₁₋₄alkyl-S(O)m-N(R³)—,wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl are optionallysubstituted with halo, C₁₋₃ alkyl, hydroxy, oxo, C₁₋₄ alkoxy-, C₁₋₄alkyl-S(O)m-, C₃₋₇ cycloalkyl-, cyano, indanyl,1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl,oxopyrrolidinyl, oxopiperidyl, Q¹—, Q¹—C(═O)—, Q¹—O—, Q¹—S(O)m-, Q¹—C₁₋₄alkyl-O—, Q¹—C₁₋₄ alkyl-S(O)m-, Q¹—C₁₋₄alkyl-C(═O)—N(R³)—, orC₁₋₄alkyl-C(═O)—N(R³)—; Q¹ is a 5-12 membered monocyclic or bicyclicaromatic ring optionally containing up to 4 heteroatoms selected from O,N and S, and is optionally substituted with halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄ alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino,cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl,aminosulfonyl, C₁₋₄ alkylC(═O)—, HO(O═)C—, C₁₋₄ alkyl-O(O)C—,R³N(R⁴)C(═O)—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)—or NH₂(HN═)C—;

[0156] A is a 5-6 membered monocyclic aromatic ring optionallycontaining up to 2 heteroatoms selected from O, N, and S, wherein said5-6 membered monocyclic aromatic ring is optionally substituted with upto 2 substituents selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy and halo-substituted C₁₋₄ alkoxy;

[0157] B is C₃₋₇ cycloalkylene or C₁₋₆ alkylene optionally substitutedwith an oxo group or C₁₋₃ alkyl;

[0158] W is NH, N—C₁₋₄ alkyl, O or N—OH;

[0159] R² is H or C₁₋₄ alkyl;

[0160] Z is a 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 3 heteroatoms selected from, N and S,wherein said 5-12 membered monocyclic or bicyclic aromatic ring isoptionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, C₁₋₄ alkenyl, hydroxy, C₁₋₄ alkoxy, nitro, amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄ alkylC(═O)—,R³C(═O)N(R⁴)—, HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino,C₁₋₄ alkyl-C(═O)NH—, Q²—S(O)m-, Q²—O—, Q²—N(R³)— or Q²—;

[0161] L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, mono- or di-(C₁₋₄ alkyl)amino, halo-substituted C₁₋₄ alkoxy,cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl,aminosulfonyl, C₁₋₄ alkylC(═O)—, HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)—, R³N(R⁴)C(═O)—,R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—, Q²—O—, Q²—C₁₋₄alkyl-O—, or two adjacent Lgroups are optionally joined together to form an alkylene chain having 3or 4 members in which one or two (non-adjacent) carbon atoms areoptionally replaced by oxygen atoms;

[0162] m is 0 or 2;

[0163] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0164] Q² is a 5-12 membered monocyclic or bicyclic aromatic ring, or a8-12 membered tricyclic ring optionally containing up to 3 heteroatomsselected from O, N and S, wherein said 5-12 membered monocyclic orbicyclic aromatic ring is optionally substituted with halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, mono- or di-(C₁₋₄alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, C₁₋₄ alkyl-(O═)C—, R³(R⁴)C(═O)N—,HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkylor C₁₋₄ alkyl-C(═O)NH—.

[0165] A further preferred group of compounds of the present inventionincludes compounds of formula (I) wherein

[0166] Y¹, Y², Y³, and Y⁴ are independently selected from N, CH andC(L);

[0167] R¹ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkyl,Q¹—, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino,mono- or di-(C₁₋₈ alkyl)amino, wherein said C₁₋₈ alkyl is optionallysubstituted with halo, C¹⁻³ alkyl, hydroxy, oxo, C₁₋₄ alkoxy-, C₁₋₄alkyl-S(O)m-, C₃₋₇ cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl,oxopyrrolidinyl, oxopiperidyl, Q¹—, Q¹—C(O)—, Q¹—O—, Q¹—S—, Q¹—C₁₋₄alkyl-O—, or C₁₋₄alkyl-C(O)—N(R³)—;

[0168] Q¹ is a 5-12 membered monocyclic aromatic ring optionallycontaining up to 4 heteroatoms selected from N and S, and is optionallysubstituted with halo, C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl and C₁₋₄alkylC(═O)—;

[0169] A is 5-6 membered monocyclic aromatic ring optionally substitutedwith halo, C₁₋₄ alkyl or C₁₋₄ alkoxy;

[0170] B is C₃₋₇ cycloalkylene or C₁₋₆ alkylene optionally substitutedwith an oxo group or C₁₋₃ alkyl;

[0171] W is NH, N—C₁₋₄ alkyl, O or N—OH;

[0172] R² is H or C₁₋₄ alkyl;

[0173] Z is 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 3 heteroatoms selected from, N and S,wherein said 5-12 membered monocyclic or bicyclic aromatic ring isoptionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, C₁₋₄ alkenyl, C₁₋₄ alkoxy, nitro, amino, cyano, R³C(═O)N(R⁴)—,C₁₋₄ alkyl-O(O═)C—, Q²—S(O)m-, Q²—O—, Q²—N(R³)— or Q²—;

[0174] L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, mono- or di-(C₁₋₄ alkyl)amino,cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O)—, HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇cycloalkyl, R³C(═O)N(R⁴)—, R³N(R⁴)C(═O)—, R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—,Q²—O—, Q²—C₁₋₄alkyl-O—, or two adjacent L groups are optionally joinedtogether to form an alkylene chain having 3 or 4 members in which one ortwo (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;

[0175] m is 0 or 2;

[0176] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0177] Q² is a 5 or 6 membered monocyclic aromatic ring, or a 8-12membered tricyc lic ring containing up to 3 heteroatoms selected from Nand S, wherein said 5 or 6 membered monocyclic aromatic ring isoptionally substituted with halo.

[0178] A further preferred group of compounds of the present inventionincludes compounds of formula (I) wherein

[0179] Y¹, Y², Y³ and Y⁴ are independently selected from N, CH and C(L);

[0180] R¹ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl or C₃₋₇cycloalkyl, wherein said C₁₋₈ alkyl is optionally substituted with halo,C₁₋₃ alkyl, hydroxy, oxo, C₁₋₄ alkoxy-, C₁₋₄ alkyl-S(O)m-, C₃₋₇cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl,oxopiperidyl, Q¹—, Q¹—C(═O)—, Q¹—O—, Q¹—S—, Q¹—C₁₋₄ alkyl-O—, orC₁₋₄alkyl-C(O)—N(R³)—;

[0181] Q¹ is a 5 or 6 membered monocyclic aromatic ring optionallycontaining up to 4 heteroatoms selected from N and S;

[0182] A is 5-6 membered monocyclic aromatic ring system optionallysubstituted with halo or C₁₋₄ alkyl;

[0183] B is or C₃₋₇ cycloalkylene or C₁₋₆ alkylene optionallysubstituted with an oxo group or C₁₋₃ alkyl;

[0184] W is NH, N—C₁₋₄ alkyl, O or N—OH;

[0185] R² is H or C₁₋₄ alkyl;

[0186] Z is 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 3 heteroatoms selected from N and S, whereinsaid 5-12 membered monocyclic or bicyclic aromatic ring is optionallysubstituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄alkenyl, C₁₋₄ alkoxy, nitro, amino, cyano, R³C(═O)N(R⁴)—, C₁₋₄alkyl-O(O═)C—, Q²—S(O)m-, Q²—O—, Q²—N(R³)— or Q²—;

[0187] L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, C₁₋₄ alkylC(═O), HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)NR⁴—,R³N(R⁴)C(═O)—, R³N(R⁴)S(O)m-, Q²—, Q²—C (═O)—, Q²—O—, Q²—C₁₋₄alkyl-O—,or two adjacent L groups are optionally joined together to form analkylene chain having 3 or 4 members in which one or two (non-adjacent)carbon atoms are optionally replaced by oxygen atoms;

[0188] m is 0 or 2;

[0189] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0190] Q² is 5 or 6 membered monocyclic aromatic ring or a 8-12 memberedtricyclic ring optionally containing 1 sulfur atom wherein said 5 or 6membered mono cyclic aromatic ring is optionally substituted with halo.

[0191] A further preferred group of compounds of the present inventionincludes compounds of formula (I) wherein

[0192] Y¹, Y², Y³ and Y⁴ are independently selected from N, CH and C(L);

[0193] R¹ is C₁₋₅ alkyl or C₃₋₇ cycloalkyl, wherein said C₁₋₅ alkyl isoptionally substituted with C₁₋₃ alkyl, hydroxy, oxo, pyrrolidinyl,piperidyl, oxopyrrolidinyl, oxopiperidyl, Q¹—, or C₁₋₄alkyl-C(O)—N(H)—;

[0194] Q¹ is 5-12 membered monocyclic aromatic ring system optionallycontaining up to 2 heteroatoms selected from N and S,

[0195] A is 5-6 membered monocyclic aromatic ring system;

[0196] B is C₁₋₃ alkylene optionally substituted with C₁₋₃ alkyl;

[0197] W is NH, N—C₁₋₂ alkyl or O;

[0198] R² is H;

[0199] Z is 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 3 heteroatoms selected from N and S, whereinsaid 5-12 membered monocyclic aromatic ring is optionally substitutedwith halo, C₁₋₄ alkyl, nitro, R³C(═O)N(R⁴)— or Q²—;

[0200] L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, cyano, HO—C₁₋₄ alkyl, acetyl,R³N(R⁴)C(═O)—,

[0201] R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—, or two adjacent L groups arejoined together to form a methylenedioxy group;

[0202] R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; and

[0203] Q² is 5 or 6 membered monocyclic aromatic ring system.

[0204] A further preferred group of compounds of the present inventionincludes compounds of formula (I) wherein

[0205] Y¹, Y², Y³ and Y⁴ are independently selected from N, CH and C—L;

[0206] R¹ is C₁₋₅ alkyl optionally substituted with C₁₋₃ alkyl, hydroxy,oxo, 5 or 6 membered monocyclic aromatic ring, wherein said 5 or 6membered monocyclic aromatic ring is containing 1 or 2 heteroatomsselected from N and S, or C₁₋₄alkyl-C(O)—N(R³)—;

[0207] A is phenyl;

[0208] B is C₁₋₂ alkylene optionally substituted with methyl;

[0209] W is NH, N—CH₃ or O;

[0210] R² is H;

[0211] Z is 5-10 membered monocyclic or bicyclic aromatic ringoptionally containing up to 3 heteroatoms selected from N and S, whereinsaid 5-10 membered monocyclic aromatic ring is optionally substitutedwith chloro, bromo, methyl, nitro, CH₃C(═O)NH—, tBuC(═O)NH— or phenyl;and

[0212] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano,acetyl, —C(═O)NH₂, trifuluoromethyloxy, methanesulfonyl, or1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined togetherto form a methylenedioxy group.

[0213] A further preferred group of compounds of the present inventionincludes compounds of formula (I) wherein

[0214] Y¹, Y², Y³ and Y⁴ are independently selected from N, CH and C—L;

[0215] R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl,pyridyl, or 1-acetylamino-1-methylethyl;

[0216] A is phenyl;

[0217] B is ethylene or propylene;

[0218] W is NH, N—CH₃ or O;

[0219] R² is H;

[0220] Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl,naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl,thiadiazolyl and thienyl being optionally substituted with one to threesubstituents independently selected from chloro, bromo, methyl,acetylamino, pivaloylamino, nitro and phenyl; and

[0221] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano,acetyl, —C(═O)NH₂, trifuluoromethyloxy, methanesulfonyl, or1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined togetherto form a methylenedioxy group.

[0222] A further preferred group of compounds of the present inventionincludes compounds of formula (I) wherein

[0223] Y¹, Y², Y³ and Y⁴ are selected from the group consisting of

[0224] a) Y¹ and Y³ are C(L), Y² is CH and Y⁴ is N;

[0225] b) Y¹ is CH, Y² and Y³ are C(L) and Y⁴ is N;

[0226] c) Y¹, Y² and Y³ are C(L) and Y⁴ is N;

[0227] d) Y¹ and Y³ are C(L), Y² is N and Y⁴ is CH;

[0228] e) Y¹ is C(L) and Y², Y³ and Y⁴ are CH;

[0229] f) Y¹, Y³ and Y⁴ are CH, and Y² is C(L);

[0230] g) Y¹, Y² and Y³ are CH, and Y⁴ is C(L);

[0231] h) Y¹ and Y² are C(L), and Y³ and Y⁴ are CH;

[0232] i) Y¹ and Y³ are C(L), and Y² and Y⁴ are CH;

[0233] j) Y¹ and Y⁴ are CH, and Y² and Y³ are C(L);

[0234] k) Y¹ and Y² are CH, Y³ is C(L) and Y⁴ is N;

[0235] l) Y¹ and Y³ are CH, Y² is C(L) and Y⁴ is N;

[0236] m) Y¹, Y², Y³ and Y⁴ are CH;

[0237] n) Y¹ and Y² are C(L), Y³ is CH and Y⁴ is N;

[0238] o) Y¹, Y² and Y⁴ are CH, and Y³ is C(L);

[0239] p) Y¹ and Y² are C(L), Y³ is N and Y⁴ is CH;

[0240] q) Y¹ and Y³ are C(L), and Y² and Y⁴ are N;

[0241] r) Y¹ is C(L), Y² and Y³ are CH, and Y⁴ is N; and

[0242] s) Y² is C(L), Y¹ and Y³ are CH, and Y⁴ is N;

[0243] R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl,pyridyl, or 1-acetylamino-1-methylethyl;

[0244] A is phenyl;

[0245] B is ethylene or propylene;

[0246] W is NH, N—CH₃ or O;

[0247] R² is H;

[0248] Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl,naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl,thiadiazolyl and thienyl being optionally substituted with one to threesubstituents independently selected from chloro, bromo, methyl,acetylamino, pivaloylamino, nitro and phenyl; and

[0249] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano,acetyl, —C(═O)NH₂, trifuluoromethyloxy, methanesulfonyl, or1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined togetherto form a methylenedioxy group.

[0250] A further preferred group of compounds of the present inventionincludes compounds of formula (I) wherein

[0251] Y¹, Y², Y³ and Y⁴ are selected from the group consisting of

[0252] a) Y¹ and Y³ are C(L), Y² is CH and Y⁴ is N;

[0253] b) Y¹ is CH, Y² and Y³ are C(L) and Y⁴ is N;

[0254] c) Y¹, Y² and Y³ are C(L) and Y⁴ is N;

[0255] d) Y¹ and Y³ are C(L), Y² is N and Y⁴ is CH;

[0256] e) Y¹ is C(L) and Y², Y³ and Y⁴ are CH;

[0257] f) Y¹, Y³ and Y⁴ are CH, and Y² is C(L);

[0258] g) Y¹, Y² and Y³ are CH, and Y⁴ is C(L);

[0259] h) Y¹ and Y² are C(L), and Y³ and Y⁴ are CH;

[0260] i) Y¹ and Y³ are C(L), and Y² and Y⁴ are CH; and

[0261] j) Y¹ and Y⁴ are CH, and Y² and Y³ are C(L);

[0262] R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl,pyridyl, or 1-acetylamino-1-methylethyl;

[0263] A is phenyl;

[0264] B is ethylene or propylene;

[0265] W is NH, N—CH₃ or O;

[0266] R² is H;

[0267] Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl,naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl,thiadiazolyl and thienyl being optionally substituted with one to threesubstituents independently selected from chloro, bromo, methyl,acetylamino, pivaloylamino, nitro and phenyl; and

[0268] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano,acetyl, —C(═O)NH₂, trifuluoromethyloxy, methanesulfonyl, or1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined togetherto form a methylenedioxy group.

[0269] Preferred individual compounds of this invention are following:

[0270]3-(4-{2-[({[(5-chloro-1,3-dimethyl-1h-pyrazol-4-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0271]3-(4-{2-[({[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0272]N-[5-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)-1,3,4-thiadiazol-2-yl]acetamide;

[0273]6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole;

[0274]6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0275]2-ethyl-5,7-dimethyl-3-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0276]2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]propyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0277]2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate;

[0278]5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-propyl-3H-imidazo[4,5-b]pyridine;

[0279]2-isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0280]2-butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0281]2-isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0282]5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-neopentyl-3H-imidazo[4,5-b]pyridine;

[0283]5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine;

[0284]3-{4-[2-({[(4-biphenylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0285]2-ethyl-5,7-dimethyl-3-{4-[2-({[(1-naphthylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-3H-imidazo[4,5-b]pyridine;

[0286]2-ethyl-5,7-dimethyl-3-{4-[2-({[(2-naphthylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-3H-imidazo[4,5-b]pyridine;

[0287]2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0288]3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0289]3-(4-{2-[({[(4,5-dichloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0290]3-{4-[2-({[(1-benzothien-2-ylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0291]3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0292]2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0293]5,6-dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0294]5-chloro-2-ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0295]6-cyano-2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0296]2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine;

[0297]4-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;

[0298]7-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;

[0299]5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;

[0300]5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;

[0301]5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0302]2-ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0303]2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0304]4,6-dimethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;

[0305]5,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0306]5,6-dichloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0307]2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl-(4-methylphenyl)sulfonylcarbamate;

[0308]6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0309]4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamate;

[0310]5-chloro-6-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0311]6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;

[0312]2-ethyl-3-{4-[2-({[({3-[hydroxy(oxido)amino]phenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0313]3-(4-{2-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0314]n-[4-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)phenyl]-2,2-dimethylpropanamide;

[0315]3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0316]3-(4-{2-[({[(3-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0317]3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0318]3-(4-{2-[({[(5-bromo-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0319]3-(4-{2-[({[(2-bromophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0320]3-{4-[2-({[({4-chloro-3-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0321]2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;

[0322]2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0323]N-{[(2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

[0324]N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

[0325]2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;

[0326]2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(2-chlorophenyl)sulfonylcarbamate;

[0327]2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0328]2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-methyl-2-pyridinyl)sulfonylcarbamate;

[0329]2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0330]2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0331]2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0332]N-{[(2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

[0333]2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0334]N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-2-thiophenesulfonarnide;

[0335]2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;

[0336]2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;

[0337]2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonylcarbamate;

[0338]2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0339]2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0340](1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate;

[0341]2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0342]N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;and

[0343]N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

[0344]2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0345]2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0346]6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide; and salts thereof.

[0347] Most preferred individual compounds of this invention arefollowing:

[0348]6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole;

[0349]6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0350]2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate;

[0351]5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine;

[0352]2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0353]3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

[0354]2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0355]5,6-dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;

[0356]2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine;

[0357]5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;

[0358]5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;

[0359]5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0360]2-ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0361]2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

[0362]4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamate;and

[0363]6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;

[0364]2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;

[0365]2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0366]N-{[(2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

[0367]N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

[0368]2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;

[0369]2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(2-chlorophenyl)sulfonylcarbamate;

[0370]2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0371]2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-methyl-2-pyridinyl)sulfonylcarbamate;

[0372]2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0373]2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0374]2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbarnate;

[0375]N-{[(2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

[0376]2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0377]N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-2-thiophenesulfonamide;

[0378]2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;

[0379]2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;

[0380]2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonylcarbamate;

[0381]2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0382]2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0383](1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate;

[0384]2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0385]N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;and

[0386]N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

[0387]2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0388]2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;

[0389]6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;and

[0390] salts thereof.

General Synthesis

[0391] The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated, Y¹ toY⁴, R¹ to R⁷, A, B, W, Z, L, m, P, Q¹ and Q² in the reaction Schemes anddiscussion that follow are defined herein before.

[0392] The aryl or heteroaryl fused imidazole comopounds of Formula (I)of this invention may be prepared by a variety of synthetic methodsknown to those skilled in the art.

[0393] In a desired reaction step of the processes described hereafter,hydroxy or amino groups protection and removal of the hydroxy or aminoprotecting groups with reactants and reagents used may be carried outaccording to known procedures such as those described in ProtectiveGroups in Organic Synthesis edited by T. W. Greene et al. (John Wiley &Sons, 1991). Typical hydroxy or amino protecting groups include benzyl,C₂H₅O(C═O)—, CH₃(C═O)—, t-butyldimethylsilyl(TBS), benzyloxycarbonylrepresented as Z and t-But-O—C(═O)— represented as t-Boc or Boc.

[0394] Reaction Scheme 1 illustrates a method for the preparation of thecompound of formula (I) wherein A is phenyl, B is ethylene, W isR^(1a)-N wherein R^(1a) is H or C₁₋₄ alkyl, and R^(1b) is C₁₋₄ alkyl oraryl (hereinafter represented by Formula (Ia)).

[0395] Compound (Ia) may be prepared through the process comprising:

[0396] (a) coupling reaction of a compound of formula 1-1 with4-aminophenethylalcohol wherein X is a leaving group such as halo,mesylate(OMs) or tosylate(OTs) to give a nitroaniline compound offormula 1-2;

[0397] (b) reduction of the resulting nitroaniline compound of formula1-2 to give a diamine compound of formula 1-3;

[0398] (c) benzimidazole or imidazopyridine ring formation with thecompound of formula 1-3 to give a compound of formula 1-4;

[0399] (d) hydrolysis of the compound of formula 1-4 to give a compoundof formula 1-5; conversion of the hydroxy group of the compound 1-5 intoa suitable leaving group such as halo, OMs or OTs to give a compound offormula 1-6;

[0400] (e) amination of the compound of formula 1-6 to give an aminocompound of formula 1-7; and

[0401] (f) sulfonylurea formation with the compound of formula 1-7 togive the compound of formula (Ia).

[0402] Each reaction step is described more specifically as follows:

[0403] (a)-(b) The coupling reaction (a) may be carried out in theabsence of, or presence of a base in a reaction inert solvent or withoutsolvent. A preferred base is selected from, for example, but not limitedto, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, orhydride, such as sodium hydroxide, potassium hydroxide, sodiummethoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate,potassium carbonate, potassium fluoride, sodium hydride or potassiumhydride, or an amine such as triethylamine, tributylamine,diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridinein the presence or absence of a reaction inert solvent. Preferredreaction inert solvents include, but are not limited to, benzene,toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine,dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide(DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof.Reaction temperatures are generally in the range of −100 to 250° C.,preferably in the range of 0 to 150° C., but if necessary, lower orhigher temperature can be employed. Reaction times are, in general, from1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed. Thenthe resulting compound of formula 1-2 may be extracted and subjected toreduction to give the compound of formula 1-3. The reduction may becarried out in the presence of a suitable reducing agent in a reactioninert solvent or without solvent. A preferred reducing agent is selectedfrom, for example, but not limited to, LiAlH₄, LiBH₄, Fe, Sn or Zn. Whena reducing reagent is Fe, Sn or Zn, if desired, the reaction is carriedout under acidic conditions in the presence of water. Preferred reactioninert solvents include, but are not limited to, methanol, ethanol,diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane,1,2-dichloroethane, tetrahyrofuran, 1,4-dioxane, or mixtures thereof.Reaction temperatures are generally in the range of −100 to 250° C.,preferably in the range of 0 to 150° C., but if necessary, lower orhigher temperature can be employed. Reaction times are, in general, from1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed. Thereduction may also be carried out under known hydrogenation conditionsin the presence of a metal catalyst under hydrogen atmosphere or in thepresence of hydrogen sources such as hydrazine or formic acid. Ifdesired, the reaction is carried out under acidic conditions, forexample, in the presence of hydrochloric acid or acetic acid. Apreferred metal catalyst is selected from, for example, but not limitedto, nickel catalysts such as Raney nickel, palladium catalysts such asPd—C, platinum catalysts such as PtO₂, or ruthenium catalysts such asRuCl₂ (Ph₃P)₃. Preferred reaction inert solvents include, but are notlimited to, methanol, ethanol, ethyl acetate, THF or mixtures thereof.The reaction may be carried out at a temperature in the range from of−100 to 150° C., preferably in the range of 0° C. to 100° C., but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed.

[0404] (c) The compound of formula 1-3 may be cyclized to form abenzimidazole or imidazopyridine ring by any synthetic procedureapplicable to structure-related compounds known to those skilled in theart (for example, see Grimmett, M. R. Imidazoles and Their BenzoDerivatives: (iii) Synthesis and Applications. In ComprehensiveHeterocyclic Chemistry, Kevin T. Potts, Eds.; Pergamon Press Ltd.:Oxford, UK, 1984; Vol.5, pp457-498., Grimmett, M. R. imidazoles. InComprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds.; ElsevierScience Ltd.: Oxford, UK, 1996; Vol.3, pp77-220., Townsend L. B; Wise D.S. Bicyclo 5-6 Systems: Three Heteroatoms 2:1. In ComprehensiveHeterocyclic Chemistry II, Christopher A. Ramsden, Eds.; ElsevierScience Ltd.: Oxford, UK, 1996; Vol.7, pp283-349). For example, thecompound of formula 1-3 is reacted with an appropriate cyclizing reagentto give the compound of formula 1-4 in a reaction inert solvent in thepresence of, or absence of a coupling reagent. If desired, this reactionmay be catalyzed by an acid such as para-toluenesulfonic acid orcamphersulfonic acid. Suitable cyclizing reagents include, but are notlimited to, a carboxylic acid, an amino carboxylic acid, an acidanhydride (e.g., acetic anhydride, isobutyric anhydride, benzoicanhydride, isonicotinic anhydride and the like) a formamidine (e.g.,formamidine alkylate such as formamidine acetate), an alkyl carbonylhalide (e.g., a cycloalkyl carbonyl halide, bicyclic orbicyclic-heterocyclic-carbonyl halide, spirocarbocyclic- orspiro-heterocyclic-carbonyl halide), an aryl or an aryl alkyl carbonylhalide (e.g., phenylacethyl halide), an heteroaryl carboxylic acid(e.g., a piperidinyl carboxylic acid compound), trialkyl orthoformate(e.g., triethyl orthoformate), and the like. Suitable reaction inertsolvents include, but are not limited to, benzene, toluene, xylene,o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane,tetrahyrofuran (THF), dimethylformamide (DMF), 1,4-dioxane,dimethylsulfoxide (DMSO) or mixtures thereof. Suitable coupling reagentsare those typically used in peptide synthesis including, but are notlimited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide(DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC),benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP), diphenylphosphorylazide (DPPA), or the like. The reaction may becarried out at a temperature in the range from of −100° C. to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a few days, preferably from 30 minutesto 48 hours, however shorter or longer reaction times, if necessary, canbe employed.

[0405] (d) The hydrolysis of the compound of formula 1-4 may be carriedout by conventional procedures. The hydrolysis may be carried out bytreatment with base. A preferred base is selected from, for example, butnot limited to, an alkali or alkaline earth metal hydroxide, alkoxide,carbonate, or halide, such as sodium hydroxide, potassium hydroxide,sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodiumcarbonate, potassium carbonate or lithium iodide, in the presence orabsence of a reaction inert solvent. Preferred reaction inert solventsinclude, but are not limited to, water, methanol, ethanol, isopropanol,tetrahyrofuran (THF), benzene, toluene, xylene, o-dichlorobenzene,nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixturesthereof. Reaction temperatures are generally in the range of −100° C. to250° C., preferably in the range of 0° C. to the reflux temperature, butif necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0406] (e)-(f) Step (e) and step (f) may be carried out under conditionsknown to those skilled in the art. For example, the hydroxy group of thecompound of formula 1-5 may be converted to the halogen group using ahalogenating agent in the presence or absence of a reaction inertsolvent. Preferred halogenating agents include, but are not limited to,thionyl chloride, oxalyl chloride, para-toluenesulfonyl chloride,methanesulfonyl chloride, hydrogen halide such as hydrogen chloride orhydrogen bromide, phosphorus tri-halide such as phosphorus trichlorideor phosphorus tribromide, phosphorus penta-halide such as phosphoruspentachloride, N-halo-succinimide such as N-chlorosuccinimide (NCS) orN-bromosuccinimide (NBS), phosphorus oxychloride, trimethylsilyl halidesuch as trimethylsilyl chloride or trimethylsilyl bromide, phosphorusreagents such as triphenyl phosphine, tributyl phosphine ortriphenylphosphite in the presence of halogen source such as carbontetrachloride, carbon tetrabromide, bromine, iodine, NBS or NCS.Preferred reaction inert solvents include, but are not limited to,tetrahyrofuran (THF), benzene, toluene, xylene, o-dichlorobenzene,nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, carbontetrachloride, carbon tetrabromide or mixtures thereof. Reactiontemperatures are generally in the range of −100 to 250° C., preferablyin the range of 0° C. to the reflux temperature, but if necessary, loweror higher temperature can be employed. Reaction times are, in general,from 1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed.Alternatively, a hydroxy group of the compound of formula 1-5 may beconverted to the sulfonate group using a sulfonating agent in thepresence of, or absence of a base. Preferred sulfonating agents include,but are not limited to, para-toluenesulfonyl chloride,para-toluenesulfonic anhydride, methanesulfonyl chloride,methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or thelike in the presence of, or absence of a reaction-inert solvent. Apreferred base is selected from, for example, but not limited to, analkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide orhydride, such as sodium hydroxide, potassium hydroxide, sodiummethoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate,potassium carbonate, potassium fluoride, sodium hydride or potassiumhydride, or an amine such as triethylamine, tributylamine,diisopropylethylamine, pyridine or dimethylaminopyridine in the presenceor absence of a reaction inert solvent. Preferred reaction inertsolvents include, but are not limited to, benzene, toluene, xylene,o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane,1,2-dichloroethane, tetrahyrofuran, dimethylformamide (DMF),1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Reactiontemperatures are generally in the range of −100° C. to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed. Then, the resulting compound of formula 1-6 may be subjectedto the amination to give the compound of formula 1-7. For example, thecompound of formula 1-6 is reacted with R^(1a)-NH₂ wherein R^(1a) is asdefined herein before. The reactants may be heated together in theabsence or presence of a reaction inert solvent. Preferred reactioninert solvents include, but are not limited to, benzene, toluene,xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane,1,2-dichloroethane, or mixtures thereof. Preferably, the reactionconducted in the presence of base. A preferred base is selected from,for example, but not limited to, an alkali or alkaline earth metalhydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide,potassium hydroxide, sodium methoxide, sodium ethoxide, potassiumtert-butoxide, sodium carbonate, potassium carbonate, sodium hydride orpotassium hydride, or an amine such as triethylamine, tributylamine,diisopropylethylamine, pyridine or dimethylaminopyridine. Reactiontemperatures are generally in the range of −100 to 250° C., preferablyin the range of 0° C. to the reflux temperature, but if necessary, loweror higher temperature can be employed. Reaction times are, in general,from 1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed.

[0407] (g) The compound of formula 1-7 may be treated withZ—SO₂N(R²)C(═O)O—R^(1b), wherein R^(1b) is aryl or C₁₋₄ alkyl, orZ—SO₂NCO to give the compound of formula (Ia). The reaction may becarried out in the absence or presence of a reaction inert solvent.Preferred reaction inert solvents include, but are not limited to,benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine,dichloromethane, 1,2-dichloroethane, or mixtures thereof. If desired,the reaction may be carried out in the presence of base, such astriethyl amine, diisopropylethylamine, or N-methylmorphorine. Reactiontemperatures are generally in the range of −100 to 250° C., preferablyin the range of 0° C. to the reflux temperature, but if necessary, loweror higher temperature can be employed. Reaction times are, in general,from 1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed.

[0408] The compound of formula 1-2 may also be prepared by the Ullmanreaction as shown in Scheme 1a. A compound of formula 1a-1 may betreated with a compound of formula 1a-2 in the absence or presence of areaction inert solvent. Preferred reaction inert solvents include, butare not limited to, benzene, toluene, xylene, o-dichlorobenzene,nitrobenzene, pyridine, dimethylformamide (DMF), dimethoxyethane (DME)or mixtures thereof. Preferably, the reaction is conducted in thepresence of metal catalyst. A preferred metal catalyst is selected from,for example, but not limited to, copper and nickel. Preferably, thereaction is conducted in the presence of base. A preferred base isselected from, for example, but not limited to, an alkali or alkalineearth metal hydroxide, alkoxide, carbonate, or hydride, such as sodiumhydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide,potassium tert-butoxide, sodium carbonate, potassium carbonate, sodiumhydride or potassium hydride, or an amine such as triethylamine,tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine.Reaction temperatures are generally in the range of −100 to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed.

[0409] As shown in Scheme 1b, an intermediate compound of formula 1b-4(1-7 wherein R^(1a) is H) may be prepared through the processcomprising:

[0410] (a) azide formation; and

[0411] (b) reduction of the resulting azide compound of formula 1b-3 togive an amine compound of the formula 1b-4.

[0412] More specifically, the nucleophilic displacement with azide maybe carried out by conventional procedures in the absence or presence ofa reaction inert solvent. Preferred reaction inert solvents include, butare not limited to, benzene, toluene, xylene, o-dichlorobenzene,nitrobenzene, dichloromethane, 1,2-dichloroethane, dimethylformamide(DMF), dimethoxyethane (DME), hexamethylphosphoramide (HMPA) or mixturesthereof. Preferred azide agents are selected from, but are not limitedto, sodium azide or lithium azide. Reaction temperatures are generallyin the range of −100 to 250° C., preferably in the range of 0° C. to thereflux temperature, but if necessary, lower or higher temperature can beemployed. Reaction times are, in general, from several minutes to a day,preferably from 20 minutes to 5 hours, however shorter or longerreaction times, if necessary, can be employed.

[0413] A compound of formula 1b-3 may also be prepared by the Mitsunobureaction. The compound of formula 1b-2 may be treated withdiphenylphosphoryl azide (DPPA) or HN₃ in the presence of dialkylazodicarboxylate such as diethyl azodicarboxylate (DEAD) and phosphinereagent such as triphenylphosphine. Preferably, this reaction may becarried out in a reaction-inert solvent. Preferred reaction inertsolvents include, but are not limited to, tetrahydrofuran (THF), diethylether, dimethylformamide (DMF), benzene, toluene, xylene,o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane,dimethoxyethane (DME), or mixtures thereof. The reduction may be carriedout in the presence of a suitable reducing agent such as lithiumaluminum hydride, sodium borohydride, triethyl phosphite,triphenylphosphine, zinc, dibutyl tinhydride or diboran in a reactioninert solvent selected form, but not limited to, THF, diethyl ether,methanol, ethanol. If desired, the reaction may be carried out underacidic conditions in the presence of hydrochloric acid or acetic acid.Reaction temperatures are generally in the range of −100 to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed.

[0414] The reduction may also be carried out under known hydrogenationconditions in the presence of a metal catalyst such as Lindlarcatalysts, Raney nickel catalysts, palladium catalysts or platinumcatalysts (preferably Lindlar catalysts, palladium catalysts or platinumcatalysts). This reaction may be carried out under hydrogen atmospherein a reaction inert solvent such as methanol, ethanol, ethyl acetate orTBF. Reaction temperatures are generally in the range of −100 to 250°C., preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed.

[0415] As shown in Scheme 1c, an intermediate compound of formula1c-5(1b-4) may also be prepared through the process comprising:

[0416] (a) coupling reaction of a compound of formula 1c-1(1-1), whereinX is a leaving group such as halo, mesylate and tosylate, with a4-aminophenylacetonitrile to give a nitroaniline compound of formula1c-2;

[0417] (b) chemoselective reduction of the resulting nitroanilinecompound of formula 1c-2 to give a diamine compound of formula 1c-3;

[0418] (c) benzimidazole or imidazopyridine ring formation with thecompound of formula 1c-3 to give a compound of formula 1c-4; and

[0419] (d) reduction of the resulting compound of formula 1c-4 to givean amine compound of the formula 1c-5(1b-4).

[0420] Each reaction step is described more specifically as follows.

[0421] (a)-(b) The coupling reaction (a) may be carried out in theabsence of, or presence of a base in a reaction inert solvent or withoutsolvent. A preferred base is selected from, for example, but not limitedto, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate orhydride, such as sodium hydroxide, potassium hydroxide, sodiummethoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate,potassium carbonate, potassium fluoride, sodium hydride or potassiumhydride, or an amine such as triethylamine, tributylamine,diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridinein the presence or absence of a reaction inert solvent. Preferredreaction inert solvents include, but are not limited to, benzene,toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine,dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide(DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof.Reaction temperatures are generally in the range of −100 to 250° C.,preferably in the range of 0 to 150° C., but if necessary, lower orhigher temperature can be employed. Reaction times are, in general, from1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed.

[0422] Then the resulting compound of formula 1c-2 may be extracted andsubjected to reduction to give the compound of formula 1c-3. Thereduction may be carried out in the presence of a reducing agent in areaction inert solvent or without solvent. A preferred reducing agent isselected from, for example, but not limited to, Fe, Sn or Zn. Ifdesired, the reaction is carried out under acidic conditions in thepresence of water. Preferred reaction inert solvents include, but arenot limited to, methanol, ethanol, diglyme, benzene, toluene, xylene,o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran,1,4-dioxane, or mixtures thereof. Reaction temperatures are generally inthe range of −100 to 250° C., preferably in the range of 0 to 150° C.,but if necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0423] (c) The compound of formula 1c-3 may be cyclized to form abenzimidazole or imidazopyridine ring by any synthetic procedureapplicable to structure-related compounds known to those skilled in theart (for example, see Grimmett, M. R. Imidazoles and Their BenzoDerivatives: (iii) Synthesis and Applications. In ComprehensiveHeterocyclic Chemistry, Kevin T. Potts, Eds.; Pergamon Press Ltd.:Oxford, UK, 1984; Vol.5, pp457-498., Grimmett, M. R. Imidazoles. InComprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds.; ElsevierScience Ltd.: Oxford, UK, 1996; Vol.3, pp77-220., Townsend L. B; Wise D.S. Bicyclo 5-6 Systems: Three Heteroatoms 2:1. In ComprehensiveHeterocyclic Chemistry II, Christopher A. Ramsden, Eds.; ElsevierScience Ltd.: Oxford, UK, 1996; Vol.7, pp283-349). For example, thecompound of formula 1c-3 is reacted with an appropriate cyclizingreagent to give the compound of formula 1c-4 in a reaction inert solventin the presence of, or absence of a coupling reagent. If desired, thisreaction may be catalyzed by an acid such as para-toluenesulfonic acidor camphersulfonic acid. Suitable cyclizing reagents include, but arenot limited to, a carboxylic acid, an amino carboxylic acid, an acidanhydride (e.g., acetic anhydride, isobutyric anhydride, benzoicanhydride, isonicotinic anhydride and the like) a formamidine (e.g.,formamidine alkylate such as formamidine acetate), an alkyl carbonylhalide (e.g., a cycloalkyl carbonyl halide, bicyclic orbicyclic-heterocyclic-carbonyl halide, spirocarbocyclic- orspiro-heterocyclic-carbonyl halide), an aryl or an aryl alkyl carbonylhalide (e.g., phenylacethyl halide), an heteroaryl carboxylic acid(e.g., a piperidinyl carboxylic acid compound), carbon disulfide,trialkyl orthoformate (e.g., triethyl orthoformate), and the like.Suitable reaction inert solvents include, but are not limited to,benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene,dichloromethane, 1,2-dichloroethane, tetrahyrofuran (THF),dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) ormixtures thereof. Suitable coupling reagents are those typically used inpeptide synthesis including, but are not limited to,dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC),benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP), diphenylphosphorylazide (DPPA), or the like. The reaction may becarried out at a temperature in the range from of −100 to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a few days, preferably from 30 minutesto 48 hours, however shorter or longer reaction times, if necessary, canbe employed.

[0424] The reduction of the compound of formula 1c-4 may be carried outin the presence of a suitable reducing agent such as diboran,boran-methyl sulfide complex, or lithium aluminum hydride in a reactioninert solvent selected form, but not limited to, THF or diethyl ether.Reaction temperatures are generally in the range of −100 to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed.

[0425] The reduction of the compound of formula 1c-4 may also be carriedout under known hydrogenation conditions such as in the presence of ametal catalyst such as Raney nickel catalysts, palladium catalysts orplatinum catalysts under hydrogen atmosphere. This reaction may becarried out in a reaction inert solvent such as methanol, ethanol,chloroform or THF in the presence or absence of hydrogen chloride. Ifnecessary, this reduction may be carried out under the adequate pressurein the range from about 0.5 to 10 kg/cm², preferably in the range from 1to 6 kg/cm². Reaction temperatures are generally in the range of −100 to250° C., preferably in the range of 0° C. to the reflux temperature, butif necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0426] The compound of formula (Ia) may also be prepared from thecompound of formula 1d-1(1-7) through a carbamate compound of formula1d-2, as depicted in Scheme 1d.

[0427] The compound of formula 1d-1(1-7) may be treated with thecarbonating agents (R^(1d) is aryl or C₁₋₄ alkyl) such as alkyl or arylhaloformate, dialkyl or diaryl dicarbonate or alkyl or aryl hydrogendicarbonate in the presence or absence of a base. Suitable basesinclude, for example, an alkali or alkaline earth metal hydroxide,alkoxide, carbonate, halide or hydride, such as sodium hydroxide,potassium hydroxide, sodium methoxide, sodium ethoxide, potassiumtert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate,potassium fluoride, sodium hydride or potassium hydride, or an aminesuch as triethylamine, tributylamine, diisopropylethylamine, pyridine ordimethylaminopyridine in the presence or absence of a reaction inertsolvent. Preferred reaction inert solvents include, but are not limitedto, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine,dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide(DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof.Reaction temperatures are generally in the range of −100 to 250° C.,preferably in the range of 0 to 150° C., but if necessary, lower orhigher temperature can be employed. Reaction times are, in general, fromseveral minutes to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed.

[0428] The resulting carbamate compound of formula 1d-2 may reacted withthe sulfonamide compound in the presence of a base such as listed abovein a reaction inert solvent as listed above (preferably DMF). Reactiontemperatures are generally in the range of −100 to 250° C., preferablyin the range of 0 to 150° C., but if necessary, lower or highertemperature can be employed. Reaction times are, in general, from 1minute to a day, preferably from 20 minutes to 5 hours, however shorteror longer reaction times, if necessary, can be employed.

[0429] As shown in Scheme 1e, an intermediate compound of formula 1e-5(1b-4) may also be prepared through the process comprising:

[0430] (a) coupling reaction of a compound of formula 1e-1 (1-1),wherein X is a leaving group such as halo, mesylate, tosylate, andtriflate with a protected 4-aminophenylethylamine to give a nitroanilinecompound of formula 1e-2;

[0431] (b) reduction of the resulting nitroaniline compound of formula1e-2 to give a diamine compound of formula 1e-3;

[0432] (c) benzimidazole or imidazopyridine ring formation with thecompound of formula 1e-3 to give a compound of formula 1e-4; and

[0433] (d) deprotection of the resulting compound of formula 1e-4 togive an amine compound of the formula 1e-5 (1b-4).

[0434] Each reaction step is described more specifically as follows.

[0435] (a)-(b) The coupling reaction (a) may be carried out in theabsence of, or presence of a base in a reaction inert solvent. Apreferred base is selected from, for example, but not limited to, analkali or alkaline earth metal hydroxide, alkoxide, carbonate, orhydride, such as sodium hydroxide, potassium hydroxide, sodiummethoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate,potassium carbonate, sodium hydride or potassium hydride, or an aminesuch as triethylamine, tributylamine, diisopropylethylamine,2,6-lutidine, pyridine or dimethylaminopyridine in the presence of areaction inert solvent. Preferred reaction inert solvents include, butare not limited to, benzene, toluene, xylene, o-dichlorobenzene,nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane,tetrahyrofuran, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide(DMSO) or mixtures thereof. Reaction temperatures are generally in therange of −100 to 250° C., preferably in the range of 0 to 150° C., butif necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed. Then the resulting compound of formula 1e-2may be extracted and subjected to reduction to give the compound offormula 1e-3. The reduction may be carried out in the presence of areducing agent in a reaction inert solvent. A preferred reducing agentis selected from, for example, but not limited to, Fe, Sn or Zn. Ifdesired, the reaction is carried out under acidic conditions in thepresence of water. Preferred reaction inert solvents include, but arenot limited to, methanol, ethanol, diglyme, benzene, toluene, xylene,o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran,1,4-dioxane, or mixtures thereof. Reaction temperatures are generally inthe range of −100 to 250° C., preferably in the range of 0 to 150° C.,but if necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed. The reduction may also be carried out underknown hydrogenation conditions in the presence of a metal catalyst underhydrogen atmosphere or in the presence of hydrogen sources such ashydrazine or formic acid. If desired, the reaction is carried out underacidic conditions, for example, in the presence of hydrochloric acid oracetic acid. A preferred metal catalyst is selected from, for example,but not limited to, nickel catalysts such as Raney nickel, palladiumcatalysts such as Pd—C, platinum catalysts such as PtO₂, or rutheniumcatalysts such as RuCl₂.(Ph₃P)₃. Preferred reaction inert solventsinclude, but are not limited to, methanol, ethanol, ethyl acetate, THFor mixtures thereof. The reaction may be carried out at a temperature inthe range from of −100 to 150° C., preferably in the range of 0° C. to100° C., but if necessary, lower or higher temperature can be employed.Reaction times are, in general, from 1 minute to a day, preferably from20 minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0436] (c) The compound of formula 1e-3 may be cyclized to form abenzimidazole or imidazopyridine ring by any synthetic procedureapplicable to structure-related compounds known to those skilled in theart (for example, see Grimmett, M. R. Imidazoles and Their BenzoDerivatives: (iii) Synthesis and Applications. In ComprehensiveHeterocyclic Chemistry, Kevin T. Potts, Eds.; Pergamon Press Ltd.:Oxford, UK, 1984; Vol.5, pp457-498., Grimmett, M. R. Imidazoles. InComprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds.; ElsevierScience Ltd.: Oxford, UK, 1996; Vol.3, pp77-220., Townsend L. B; Wise D.S. Bicyclo 5-6 Systems: Three Heteroatoms 2:1. In ComprehensiveHeterocyclic Chemistry II, Christopher A. Ramsden, Eds.; ElsevierScience Ltd.: Oxford, UK, 1996; Vol.7, pp283-349). For example, thecompound of formula 1e-3 is reacted with an appropriate cyclizingreagent to give the compound of formula 1e-4 in a reaction inert solventin the presence of, or absence of a coupling reagent. If desired, thisreaction may be catalyzed by an acid such as para-toluenesulfonic acidor camphersulfonic acid. Suitable cyclizing reagents include, but arenot limited to, a carboxylic acid, an amino carboxylic acid, an acidanhydride (e.g., acetic anhydride, isobutyric anhydride, benzoicanhydride, isonicotinic anhydride and the like) a formamidine (e.g.,formamidine alkylate such as formamidine acetate), an alkyl carbonylhalide (e.g., a cycloalkyl carbonyl halide, bicyclic orbicyclic-heterocyclic-carbonyl halide, spirocarbocyclic- orspiro-heterocyclic-carbonyl halide), an aryl or an aryl alkyl carbonylhalide (e.g., phenylacethyl halide), an heteroaryl carboxylic acid(e.g., a piperidinyl carboxylic acid compound), carbon disulfide,trialkyl orthoformate (e.g., triethyl orthoformate), and the like.Suitable reaction inert solvents include, but are not limited to,benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene,dichloromethane, 1,2-dichloroethane, tetrahyrofuran (THF),dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) ormixtures thereof. Suitable coupling reagents are those typically used inpeptide synthesis including, but are not limited to,dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC),benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP), diphenylphosphorylazide (DPPA), or the like. The reaction may becarried out at a temperature in the range from of −100 to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a few days, preferably from 30 minutesto 48 hours, however shorter or longer reaction times, if necessary, canbe employed.

[0437] (d) The deprotection of the compound of formula 1e-4 may becarried out according to known procedures such as those described inProtective Groups in Organic Synthesis edited by T. W. Greene et al.(John Wiley & Sons, 1991). Typical amino protecting groups includebenzyl represented as Bn, benzyloxycarbonyl represented as Cbz or Z andt-But-O—C(═O)— represented as t-Boc or Boc. In the case of Bn or Zprotection, the removal of the amino protecting groups may be carriedout under, for example, but not limited to, known hydrogenolysisconditions in the presence of a metal catalyst under hydrogen atmosphereor in the presence of hydrogen sources such as formic acid or ammoniumformate in a reaction inert solvent. If desired, the reaction is carriedout under acidic conditions, for example, in the presence ofhydrochloric acid or acetic acid. A preferred metal catalyst is selectedfrom, for example, but not limited to, palladium catalysts such as Pd—C.Preferred reaction inert solvents include, but are not limited to,methanol, ethanol, ethyl acetate, THF or mixtures thereof. The reactionmay be carried out at a temperature in the range from of −100 to 150°C., preferably in the range of 0° C. to 100° C., but if necessary, loweror higher temperature can be employed. Reaction times are, in general,from 1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed. In thecase of Boc protection, the removal of the amino protecting groups maybe carried out under, for example, but not limited to, known acidhydrolysis conditions in a reaction inert solvent or without solvent. Ifdesired, the reaction is carried out under acidic conditions, forexample, in the presence of hydrochloric acid or trifluoroacetic acidwith a reaction inert scavenger of t-butyl cations. Preferred reactioninert scavenger of t-butyl cations include, but are not limited to,benzene, thiophenol, anisole, thioanisole, thiocresole, cresole, ordimethyl sulfide. Preferred reaction inert solvents include, but are notlimited to, methanol, ethanol, ethyl acetate, dioxane or mixturesthereof. The reaction may be carried out at a temperature in the rangefrom of −100 to 150° C., preferably in the range of 0° C. to 100° C.,but if necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0438] Reaction Scheme if illustrates a method for the preparation ofthe compound of formula (I) wherein W is R^(1a)-N wherein R^(1a) is H orC₁₋₄ alkyl, and R^(1b) is C₁₋₄ alkyl or aryl (hereinafter represented byFormula (If).

[0439] Compound (If) may be prepared through the process comprising:

[0440] (a) coupling reaction of a compound of formula 1f-1 with acompound of formula 1f-0 wherein X is a leaving group such as halo,mesylate(OMs) or tosylate(OTs) to give a nitroaniline compound offormula 1f-2;

[0441] (b) reduction of the resulting nitroaniline compound of formula1f-2 to give a diamine compound of formula 1f-3;

[0442] (c) benzimidazole or imidazopyridine ring formation with thecompound of formula 1f-3 to give a compound of formula 1f-4;

[0443] (d) hydrolysis of the compound of formula 1f-4 to give a compoundof formula 1f-5; conversion of the hydroxy group of the compound 1f-5into a suitable leaving group such as halo, OMs or OTs to give acompound of formula 1f-6;

[0444] (e) amination of the compound of formula 1f-6 to give an aminocompound of formula 1f-7; and

[0445] (f) sulfonylurea formation with the compound of formula 1f-7 togive the compound of formula (If).

[0446] Each reaction step is described more specifically as follows:

[0447] (a)-(b) The coupling reaction (a) may be carried out in theabsence of, or presence of a base in a reaction inert solvent or withoutsolvent. A preferred base is selected from, for example, but not limitedto, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate,halide or hydride, such as sodium hydroxide, potassium hydroxide, sodiummethoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate,potassium carbonate, potassium fluoride, sodium hydride or potassiumhydride, or an amine such as triethylamine, tributylamine,diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridinein the presence or absence of a reaction inert solvent. Preferredreaction inert solvents include, but are not limited to, benzene,toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine,dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide(DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof.Reaction temperatures are generally in the range of −100 to 250° C.,preferably in the range of 0 to 150° C., but if necessary, lower orhigher temperature can be employed. Reaction times are, in general, from1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed. Thenthe resulting compound of formula 1f-2 may be extracted and subjected toreduction to give the compound of formula 1f-3. The reduction may becarried out in the presence of a suitable reducing agent in a reactioninert solvent or without solvent. A preferred reducing agent is selectedfrom, for example, but not limited to, LiAlH₄, LiBH₄, Fe, Sn or Zn. Whena reducing reagent is Fe, Sn or Zn, if desired, the reaction is carriedout under acidic conditions in the presence of water. Preferred reactioninert solvents include, but are not limited to, methanol, ethanol,diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane,1,2-dichloroethane, tetrahyrofuran, 1,4-dioxane, or mixtures thereof.Reaction temperatures are generally in the range of −100 to 250° C.,preferably in the range of 0 to 150° C., but if necessary, lower orhigher temperature can be employed. Reaction times are, in general, from1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed. Thereduction may also be carried out under known hydrogenation conditionsin the presence of a metal catalyst under hydrogen atmosphere or in thepresence of hydrogen sources such as hydrazine or formic acid. Ifdesired, the reaction is carried out under acidic conditions, forexample, in the presence of hydrochloric acid or acetic acid. Apreferred metal catalyst is selected from, for example, but not limitedto, nickel catalysts such as Raney nickel, palladium catalysts such asPd—C, platinum catalysts such as PtO₂, or ruthenium catalysts such asRuCl₂ (Ph₃P)₃. Preferred reaction inert solvents include, but are notlimited to, methanol, ethanol, ethyl acetate, THF or mixtures thereof.The reaction may be carried out at a temperature in the range from of−100 to 150° C., preferably in the range of 0° C. to 100° C., but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed.

[0448] (c) The compound of formula 1f-3 may be cyclized to form abenzimidazole or imidazopyridine ring by any synthetic procedureapplicable to structure-related compounds known to those skilled in theart (for example, see Grimmett, M. R. Imidazoles and Their BenzoDerivatives: (iii) Synthesis and Applications. In ComprehensiveHeterocyclic Chemistry, Kevin T. Potts, Eds.; Pergamon Press Ltd.:Oxford, UK, 1984; Vol.5, pp457-498., Grimmett, M. R. Irnidazoles. InComprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds.; ElsevierScience Ltd.: Oxford, UK, 1996; Vol.3, pp77-220., Townsend L. B; Wise D.S. Bicyclo 5-6 Systems: Three Heteroatoms 2:1. In ComprehensiveHeterocyclic Chemistry II, Christopher A. Ramsden, Eds.; ElsevierScience Ltd.: Oxford, UK, 1996; Vol.7, pp283-349). For example, thecompound of formula 1f-3 is reacted with an appropriate cyclizingreagent to give the compound of formula 1f-4 in a reaction inert solventin the presence of, or absence of a coupling reagent. If desired, thisreaction may be catalyzed by an acid such as para-toluenesulfonic acidor camphersulfonic acid. Suitable cyclizing reagents include, but arenot limited to, a carboxylic acid, an amino carboxylic acid, an acidanhydride (e.g., acetic anhydride, isobutyric anhydride, benzoicanhydride, isonicotinic anhydride and the like) a formamidine (e.g.,formamidine alkylate such as formamidine acetate), an alkyl carbonylhalide (e.g., a cycloalkyl carbonyl halide, bicyclic orbicyclic-heterocyclic-carbonyl halide, spirocarbocyclic- orspiro-heterocyclic-carbonyl halide), an aryl or an aryl alkyl carbonylhalide (e.g., phenylacethyl halide), an heteroaryl carboxylic acid(e.g., a piperidinyl carboxylic acid compound), trialkyl orthoformate(e.g., triethyl orthoformate), and the like. Suitable reaction inertsolvents include, but are not limited to, benzene, toluene, xylene,o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane,tetrahyrofuran (THF), dimethylformamide (DMF), 1,4-dioxane,dimethylsulfoxide (DMSO) or mixtures thereof. Suitable coupling reagentsare those typically used in peptide synthesis including, but are notlimited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide(DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC),benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP), diphenylphosphorylazide (DPPA), or the like. The reaction may becarried out at a temperature in the range from of −100° C. to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a few days, preferably from 30 minutesto 48 hours, however shorter or longer reaction times, if necessary, canbe employed.

[0449] (d) The hydrolysis of the compound of formula 1f-4 may be carriedout by conventional procedures. The hydrolysis may be carried out bytreatment with base. A preferred base is selected from, for example, butnot limited to, an alkali or alkaline earth metal hydroxide, alkoxide,carbonate, or halide, such as sodium hydroxide, potassium hydroxide,sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodiumcarbonate, potassium carbonate or lithium iodide, in the presence orabsence of a reaction inert solvent. Preferred reaction inert solventsinclude, but are not limited to, water, methanol, ethanol, isopropanol,tetrahyrofuran (THF), benzene, toluene, xylene, o-dichlorobenzene,nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixturesthereof. Reaction temperatures are generally in the range of −100° C. to250° C., preferably in the range of 0° C. to the reflux temperature, butif necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0450] (e)-(f) Step (e) and step (f) may be carried out under conditionsknown to those skilled in the art. For example, the hydroxy group of thecompound of formula 1f-5 may be converted to the halogen group using ahalogenating agent in the presence or absence of a reaction inertsolvent. Preferred halogenating agents include, but are not limited to,thionyl chloride, oxalyl chloride, para-toluenesulfonyl chloride,methanesulfonyl chloride, hydrogen halide such as hydrogen chloride orhydrogen bromide, phosphorus tri-halide such as phosphorus trichlorideor phosphorus tribromide, phosphorus penta-halide such as phosphoruspentachloride, N-halo-succinimide such as N-chlorosuccinimide (NCS) orN-bromosuccinimide (NBS), phosphorus oxychloride, trimethylsilyl halidesuch as trimethylsilyl chloride or trimethylsilyl bromide, phosphorusreagents such as triphenyl phosphine, tributyl phosphine ortriphenylphosphite in the presence of halogen source such as carbontetrachloride, carbon tetrabromide, bromine, iodine, NBS or NCS.Preferred reaction inert solvents include, but are not limited to,tetrahyrofuran (THF), benzene, toluene, xylene, o-dichlorobenzene,nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, carbontetrachloride, carbon tetrabromide or mixtures thereof. Reactiontemperatures are generally in the range of −100 to 250° C., preferablyin the range of 0° C. to the reflux temperature, but if necessary, loweror higher temperature can be employed. Reaction times are, in general,from 1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed.Alternatively, a hydroxy group of the compound of formula 1f-5 may beconverted to the sulfonate group using a sulfonating agent in thepresence of, or absence of a base. Preferred sulfonating agents include,but are not limited to, para-toluenesulfonyl chloride,para-toluenesulfonic anhydride, methanesulfonyl chloride,methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or thelike in the presence of, or absence of a reaction-inert solvent. Apreferred base is selected from, for example, but not limited to, analkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide orhydride, such as sodium hydroxide, potassium hydroxide, sodiummethoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate,potassium carbonate, potassium fluoride, sodium hydride or potassiumhydride, or an amine such as triethylamine, tributylamine,diisopropylethylamine, pyridine or dimethylaminopyridine in the presenceor absence of a reaction inert solvent. Preferred reaction inertsolvents include, but are not limited to, benzene, toluene, xylene,o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane,1,2-dichloroethane, tetrahyrofuran, dimethylformamide (DMF),1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Reactiontemperatures are generally in the range of −100° C. to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed. Then, the resulting compound of formula 1f-6 may be subjectedto the amination to give the compound of formula 1f-7. For example, thecompound of formula 1f-6 is reacted with R^(1a)—NH₂ wherein R^(1a) is asdefined herein before. The reactants may be heated together in theabsence or presence of a reaction inert solvent. Preferred reactioninert solvents include, but are not limited to, benzene, toluene,xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane,1,2-dichloroethane, or mixtures thereof. Preferably, the reactionconducted in the presence of base. A preferred base is selected from,for example, but not limited to, an alkali or alkaline earth metalhydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide,potassium hydroxide, sodium methoxide, sodium ethoxide, potassiumtert-butoxide, sodium carbonate, potassium carbonate, sodium hydride orpotassium hydride, or an amine such as triethylamine, tributylamine,diisopropylethylamine, pyridine or dimethylaminopyridine. Reactiontemperatures are generally in the range of −100 to 250° C., preferablyin the range of 0° C. to the reflux temperature, but if necessary, loweror higher temperature can be employed. Reaction times are, in general,from 1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed.

[0451] (g) The compound of formula 1f-7 may be treated withZ—SO₂N(R²)C(═O)O—R^(1b), wherein R^(1b) is aryl or C₁₋₄ alkyl, orZ—SO₂NCO to give the compound of formula (If). The reaction may becarried out in the absence or presence of a reaction inert solvent.Preferred reaction inert solvents include, but are not limited to,benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine,dichloromethane, 1,2-dichloroethane, or mixtures thereof. If desired,the reaction may be carried out in the presence of base, such astriethyl amine, diisopropylethylamine, or N-methylmorphorine. Reactiontemperatures are generally in the range of −100 to 250° C., preferablyin the range of 0° C. to the reflux temperature, but if necessary, loweror higher temperature can be employed. Reaction times are, in general,from 1 minute to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed.

[0452] As described in scheme 2, the compound of formula (I), wherein Ais phenyl, B is ethylene and W is NH (hereinafter represented by Formula(Ib)), may be prepared through the process comprising:

[0453] (a) coupling reaction of a compound of formula 2-1(1-1), whereinX is a leaving group such as halo, mesylate or tosylate with2-(4-aminophenyl)propionic acid or ester (2-2) (when using esterderivative of 2-2, followed by hydrolysis) to give a nitroanilinecompound of formula 2-3;

[0454] (b) Curutius rearrangement of the compound of formula 2-3followed by treating with an alcohol or a phenol to give a carbamatecompound of formula 2-5;

[0455] (c) sulfonylurea formation with compound of formula 2-5 to give acompound of formula 2-6;

[0456] (d) reduction of the resulting nitroaniline compound of formula2-6 to give a diamine compound of formula 2-7; and

[0457] (e) benzimidazole or imidazopyridine ring formation with thecompound of formula 2-7 to give a compound of formula (Ib);

[0458] Each reaction step is described more specifically as follows.

[0459] (a) The compound of formula 2-3 may be prepared from the compoundof 2-1(1-1) according to the similar procedure to that of described inScheme 1.

[0460] (b) Curutius rearrangement of the compound of formula 2-3 may becarried out by conventional procedures. In a typical procedure, therearrangement is carried out by treatment with DPPA in the presence of abase in a reaction inert solvent. Suitable bases include, for example,an amine such as triethylamine, tributylamine, diisopropylethylamine,pyridine or dimethylaminopyridine. Preferred reaction inert solventsinclude, but are not limited to, benzene, toluene, xylene,o-dichlorobenzene, nitrobenzene, tetrahyrofuran (ThF), 1,4-dioxane, ormixtures thereof. Reaction temperatures are generally in the range of 0to 250° C., preferably in the range of 25° C. to the reflux temperature,but if necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0461] The obtained isocyanate 2-4 may be treated with an alcohol or aphenol to give the compound of formula 2-5. Reaction temperatures aregenerally in the range of 0 to 250° C., preferably in the range of 25°C. to the reflux temperature, but if necessary, lower or highertemperature can be employed. Reaction times are, in general, fromseveral minutes to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed.

[0462] (c) Treatment of the obtained carbamate compound of formula 2-5with sulfonamide in the presence or absence of a base may give thecompound of formula 2-6. Suitable bases include, for example, an alkalior alkaline earth metal hydroxide, alkoxide, carbonate, halide orhydride, such as sodium hydroxide, potassium hydroxide, sodiummethoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate,potassium carbonate, cesium carbonate, potassium fluoride, sodiumhydride or potassium hydride in the presence or absence of a reactioninert solvent. Preferred reaction inert solvents include, but are notlimited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene,dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide(DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof.Reaction temperatures are generally in the range of −100° C. to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed.

[0463] (d) and (e) The reduction of the compound 2-6 and the followingring formation may be carried out in an analogous manner to those ofdescribed in Scheme 1 to give the compound of formula (Ib).

[0464] As shown in Scheme 2a, an intermediate compound of formula 2a-3(2-7) may also be prepared through the procedure comprising:

[0465] (a) reduction of the above obtained compound 2a-1 (2-5) to give adiamine compound of formula 2a-2; and

[0466] (b) sulfonylurea formnation of the compound of formula 2a-2 maygive a compound of formula 2a-3 (2-7).

[0467] The reduction of the compound of formula 2a-1 (2-5), andsulfonylurea formation with the obtained compound of formula 2a-2 may becarried out by the same procedure as described in scheme 1 and 1d.

[0468] As shown in scheme 2a, a carbamate compound of formula 2a-4 maybe prepared from the compound of formula 2a-2 by the cyclizationaccording to the same procedure as described in Scheme 1.

[0469] Alternatively, an intermediate compound of formula 2b-5(2-5) mayalso be prepared from a carboxylic acid compound of formula 2b-1(2-3) bythe methods illustrated in Scheme 2b. Path A in Scheme 2b illustrates apreparation procedure for a compound of formula 2b-5 (2-5) according tothe Hoffman rearrangement (e.g., Wallis; Lane Org React. 1946, 3,267-306). The amide compound of formula 2b-2 may be prepared by knownmethods (e.g., Org. Syn. Coll Vol 4, 513 (1963)). Hoffman rearrangementof the obtained carboxamide compound of formula 2b-2 may be carried outunder the known conditions followed by treatment with an alcohol or aphenol under the same conditions described in Scheme 2 to afford thecompound of formula 2b-5 (2-5). Path B in Scheme 2b illustrates apreparation procedure for the compound of formula 2b-5 (2-5) accordingto Lossen rearrangement (e.g., Bauer; Exner Angew. Chem. Int. Ed. Engl.1974, 13, 376-384). The O-acyl hydroxamic acid compound of formula 2b-3may be prepared by known methods (e.g., Miller, Marvin J.; Mattingly,Phillip G.; Morrison, Marjorie A.; Kerwin, James F., J.Amer.Chem.Soc.,1980, 102, 7026-7032). The carboxylic acid compound of formula 2b-1(2-3) may be treated with hydroxamic acid derivative, usually O-acylhydroxamic acid, in the presence of coupling agent such asdicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC),benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP), diphenylphosphorylazide (DPPA), or the like. This reaction may becarried out at from about 0° C. to the reflux temperature of thereaction mixture, preferably from about room temperature to the refluxtemperature for about 1 minute to about 120 hours, preferably for fromabout 10 minutes to about 72 hours. Lossen rearrangement of the obtainedO-acyl hydroxamic acid compound of formula 2b-3 may be carried out underthe known conditions followed by treatment with an alcohol or a phenolunder the same conditions described in Scheme 2 to afford the compoundof formula 2b-5(2-5).

[0470] The compound of formula (Ia) may be prepared from the compound offormula (Ia1), wherein R² is H, by methods known to those skilled in theart as depicted in Scheme 3. The compound of formula (Ia1) may betreated with appropriate alkyl halides, R²-halo in the presence of abase such as lithium diisopropyl amide (LDA), sodium hydride (NaH) orpotassium t-butoxide in a reaction inert solvent such as THF or DMF atabout 0° C. to 80° C. for 20 minutes to 24 hours.

[0471] As depicted in Scheme 4, a carbamate compound of formula 4-2 maybe prepared from a compound of formula 4-1(1-5) according to the sameconditions described in Scheme 1. More specifically, the compound offormula 4-1 may be treated with Z—SO₂N(R²)C(═O)O—R^(1b) wherein R^(1b)is aryl or C₁₋₄ alkyl, or Z—SO₂NCO to give the compound of formula(4-2). The reaction may be carried out in the absence or presence of areaction inert solvent. Preferred reaction inert solvents include, butare not limited to, benzene, toluene, xylene, o-dichlorobenzene,nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixturesthereof. If desired, the reaction may be carried out in the presence ofbase, such as triethyl amine, diisopropylethylamine, orN-methylmorphorine. Reaction temperatures are generally in the range of−100° C. to 250° C., preferably in the range of 0° C. to the refluxtemperature, but if necessary, lower or higher temperature can beemployed. Reaction times are, in general, from 1 minute to a day,preferably from 20 minutes to 5 hours, however shorter or longerreaction times, if necessary, can be employed.

[0472] As shown in Scheme 5, the compound of formula (I), wherein A isphenyl, B is ethylene and W is N—OR⁷ (hereinafter represented by Formula(Id)) may be prepared through the process comprising:

[0473] (a) Mitsunobu reaction of a compound of formula 5-1 (1-5) to givea compound of formula 5-2;

[0474] (b) cleavage of the protecting group of the compound of formula5-2 to give a hydroxyamine compound of formula 5-3; and

[0475] (c) sulfonylurea formation with the compound of formula 5-3 togive a compound of formula (Id).

[0476] As shown in Scheme 4a, the compound of formula 4a-3 (4-2) mayalso be prepared by reacting a compound of formula 4a-1 with asubstituted benzene compound of formula 4a-2 to give a1-phenylbenzimidazole compound of formula 4a-3 (4-2);

[0477] The compounds of formula 4a-1 may be synthesized by any of theknown methods. The group G09 of the compounds of formula 4a-2 is aselected from a suitable displaceable group, for example, fluoro,chloro, bromo, iodo, trifluoromethanesulfonyloxy, methanesulfonyloxy,p-toluenesulfonyloxy, or boronic acid group.

[0478] The coupling reaction may be carried out in the presence of abase in a reaction inert solvent. A preferred base is selected from, forexample, but not limited to, an alkali or alkaline earth metalhydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide,potassium hydroxide, sodium methoxide, sodium ethoxide, potassiumtert-butoxide, sodium carbonate, potassium carbonate, sodium hydride orpotassium hydride, or an amine such as triethylamine, tributylamine,diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine.Preferred reaction inert solvents include, but are not limited to,benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine,dichloromethane, 1,2-dichloroethane, tetrahyrofuran, acetonitrile,dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO),1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone, or mixturesthereof. Reaction temperatures are generally in the range of −100 to250° C., preferably in the range of 0 to 150° C., but if necessary,lower or higher temperature can be employed. Reaction times are, ingeneral, from 1 minute to several weeks, preferably from 20 minutes to 1week, however shorter or longer reaction times, if necessary, can beemployed. Conveniently, the compound of formula 4a-1 may be reacted withthe compound of formula 4a-2 in the presence of a suitable catalyst toform the compound of formula 4a-3 (4-2) by any synthetic procedureapplicable to structure-related compounds known to those skilled in theliterature (e.g., Lam, P. Y. S.; Clark, C. G.; Saubern, S; Adams, J;Winters, M. P.; Chan, D. M. T.; Combs, A., Tetrahedron Lett., 1998, 39,2941-2944., Kiyomori, A.; Marcoux, J.; Buchwald, S. L., TetrahedronLett., 1999, 40, 2657-2660., Lam, P. Y. S.; Deudon, S.; Averill, K. M.;Li, R.; He, M. Y.; DeShong, P.; Clark, C. G., J. Am. Chem. Soc.,2000,122, 7600-7601., Collman, J. P.; Zhong, M., Org. Lett., 2000, 2,1233-1236.). Preferred reaction catalyst is selected from, for example,but not limited to, tetrakis(triphenylphosphine)-palladium,bis(triphenylphosphine)palladium(II) chloride, copper(O), copper(I)acetate, copper(I) bromide, copper(I) chloride, copper(I) iodide,copper(I) oxide, copper(II) trifluoromethanesulfonate, copper(H)acetate, copper(H) bromide, copper(I) chloride, copper(II) iodide,copper(II) oxide, or copper(I) trifluoromethanesulfonate.

[0479] Each reaction step is described more specifically as follows.

[0480] (a) The compound of formula 5-2 may be prepared by the Mitsunobureaction. The compound of formula 5-1 may be treated with HN(OR⁷)G¹wherein G¹ is H or a protecting group, preferably, G1 is a suitableprotecting group, for example, methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Z), phenylsulfonyl,p-toluenesulfonyl, or the like, and R⁷ is an alkyl (e.g., methyl orethyl) or G² (G² is a suitable protecting group, for example,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc),benzyloxycarbonyl(Z), phenylsulfonyl, p-toluenesulfonyl, trimethylsilyl,t-butyldimethylsilyl, or the like)). For example, the compound offormula 5-1 is reacted with [N,O-Bis-protectedhydroxylamine] (e.g.,Baillie, L. C.; Batsanov, A.; Bearder, J. R.; Whiting, D. A. J. Chem.Soc. Perkin Trans. 1, 1998, 20, 3471.) in the presence of dialkylazodicarboxylate such as diethyl azodicarboxylate (DEAD) and phosphinereagent such as triphenylphosphine. Preferably, this reaction may becarried out in a reaction-inert solvent. Preferred reaction inertsolvents include, but are not limited to, tetrahydrofuran (THF), diethylether, dimethylformamide (DMF), benzene, toluene, xylene,o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane,dimethoxyethane (DME), or mixtures thereof. Reaction temperatures aregenerally in the range of −100° C. to 250° C., preferably in the rangeof 0° C. to the reflux temperature, but if necessary, lower or highertemperature can be employed. Reaction times are, in general, from 1minute to a day, preferably from 20 minutes to 5 hours, however shorteror longer reaction times, if necessary, can be employed.

[0481] (b) Cleavage of the protecting group may be carried out by anumber of standard procedures known to those skilled in the art (e.g.,“Protection for the Hydroxy Group and the Amino Group”, in ProtectiveGroups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M.Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 10-142, 309-405).

[0482] (c) sulfonylurea formation may be carried out according to theconditions illustrated in Scheme 1. Specifically, the compound offormula 5-3 may be treated with Z—SO₂N(R²)C(═O)O—R^(1b) wherein R^(1b)is aryl or C₁₋₄ alkyl, or Z—SO₂NCO to give the compound of formula (Id).The reaction may be carried out in the absence or presence of a reactioninert solvent. Preferred reaction inert solvents include, but are notlimited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene,pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Ifdesired, the reaction may be carried out in the presence of base, suchas triethyl amine, diisopropylethylamine, or N-methylmorphorine.Reaction temperatures are generally in the range of −100° C. to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed.

[0483] Reaction Scheme 6 illustrates a method for the preparation of thecompound of formula (Ia), wherein at least one of Y¹, Y², Y³ and Y⁴ isC—CONH₂, A is phenyl, B is ethylene and W is R^(1a)—N (R^(1a) is H orC₁₋₄ alkyl) (hereinafter represented by Formula (Ia²)), and that of thecompound of formula (Ia) wherein at least one of Y¹, Y², Y³ and Y⁴ isC—CO₂H, A is phenyl and B is ethylene and W is R^(1a)—N (R^(1a) is H orC₁₋₄ alkyl) (hereinafter represented by Formula (Ia³)). Compound (Ia³)may be prepared through the process comprising:

[0484] (a) hydrolysis of a compound of formula 6-1 to give a compound offormula 6-2;

[0485] (b) conversion of the hydroxy group of the compound 6-2 into theleaving group such as halo, mesylate and tosylate to give a compound offormula 6-3;

[0486] (c) azide formation;

[0487] (d) reduction of the resulting azide compound followed bysulfonylurea formation to give the compound of formula (Ia²); and

[0488] (e) hydrolysis of the compound of formula (Ia²) to give thecompound of formula (Ia³);

[0489] Each reaction step is described more specifically as follows:

[0490] (a) Intermediate 6-1 may be prepared by the methods illustratedin Scheme 1. The hydrolysis of the compound of formula 6-1 may becarried out by conventional procedures. The hydrolysis may be carriedout by treatment with a peroxide such as hydrogen peroxide in thepresence of a base such as sodium hydroxide, potassium hydroxide,lithium hydroxide or ammonium hydroxide in a suitable solvent such asaqueous methanol, dimethylsulfoxide and tetrahydrofuran. Reactiontemperatures are generally in the range of −100° C. to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed. The hydrolysis may also be carried out by treatment with abase such as sodium hydroxide, potassium hydroxide or lithium hydroxide,or an acid such as sulfuric acid in a suitable solvent such as aqueousmethanol, aqueous ethanol, t-butanol or mixtures thereof. Reactiontemperatures are generally in the range of −100° C. to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from several minutes to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0491] (b) (c) and (d) Step (b), (c) and step (d) may be carried outaccording to the conditions illustrated in Scheme 1 and 1b.

[0492] (e) The hydrolysis of the compound of formula (Ia²) may becarried out by conventional procedures. The hydrolysis may be carriedout by treatment with a base such as sodium hydroxide, potassiumhydroxide or lithium hydroxide, or an acid such as sulfuric acid orphosphoric acid in a suitable solvent such as aqueous methanol, ethanolethylene glycol, water, tetrahydrofuran or mixtures thereof. Reactiontemperatures are generally in the range of −100° C. to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed.

[0493] Reaction Scheme 7 illustrates an alternative method for thepreparation of the compound of formula (Ia²). A compound of formula(Ia⁴) may be prepared by the methods illustrated in Scheme 1. Hydrolysisof the compound of formula (Ia⁴) may be carried out by treatment with abase such as sodium hydroxide, potassium hydroxide, lithium hydroxide orammonium hydroxide in a suitable solvent such as aqueous methanol,dimethylsulfoxide and tetrahydrofuran. Reaction temperatures aregenerally in the range of −100° C. to 250° C., preferably in the rangeof 0° C. to the reflux temperature, but if necessary, lower or highertemperature can be employed. Reaction times are, in general, from 1minute to a day, preferably from 20 minutes to 5 hours, however shorteror longer reaction times, if necessary, can be employed. The hydrolysismay also be carried out by treatment with a base such as sodiumhydroxide, potassium hydroxide or lithium hydroxide, or an acid such assulfuric acid in a suitable solvent such as aqueous methanol, aqueousethanol, t-butanol or mixtures thereof.

[0494] Reaction temperatures are generally in the range of −100° C. to250° C., preferably in the range of 0° C. to the reflux temperature, butif necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0495] Reaction Scheme 8 illustrates a method for the preparation of thecompound of formula (Ia) wherein at least one of Y¹, Y², Y³ and Y⁴ isC—OG¹ wherein G¹ is defined before, A is phenyl, B is ethylene and W isR^(1a)—N (R^(1a) is H or C₁₋₄ alkyl), (hereinafter represented byFormula (Ia⁵)) and that of the compound of formula (Ia) wherein at leastone of Y¹, Y², Y³ and Y⁴ is C—OH, A is phenyl B is ethylene and W isR^(1a)—N (R^(1a) is H or C₁₋₄ alkyl), (hereinafter represented byFormula (Ia⁶)).

[0496] Compound (Ia⁶) may be prepared through the process comprising:

[0497] (a) dealkylation of a compound of formula 8-1 to give a compoundof formula 8-2;

[0498] (b) protection of the hydroxy group of the compound 8-2 to give acompound of formula 8-3;

[0499] (c) preparation of the compound of formula (Ia⁵); and

[0500] (d) cleavage of the protecting group of the compound of formula(Ia⁵) to give the compound of formula (Ia⁶).

[0501] Each reaction step is described more specifically as follows.

[0502] (a) Intermediate 8-1, wherein R⁸ is C1-C4alkyl, may be preparedby the methods illustrated in Scheme 1. dealkylation of the compound offormula 8-1 may be carried out a number of standard procedures known tothose skilled in the art (e.g., “Protection of Phenols”, in ProtectiveGroups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M.Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 143-174). For example,the compound of formula 8-1 may be treated with a proton and/or Lewisacid such as hydrogen bromide or aluminum chloride in a suitable solventsuch as water, acetic acid or dichloromethane. Reaction temperatures aregenerally in the range of −100° C. to 250° C., preferably in the rangeof 0° C. to the reflux temperature, but if necessary, lower or highertemperature can be employed. Reaction times are, in general, from 1minute to a day, preferably from 20 minutes to 5 hours, however shorteror longer reaction times, if necessary, can be employed. The reactionmay also carried out in the presence of a thioalkoxide such as sodiumthiomethoxide, lithium thiomethoxide, sodium thioethoxide in thepresence or absence of a reaction inert solvent such as DMSO, DMF orHMPA. Reaction temperatures are generally in the range of −100° C. to250° C., preferably in the range of 0° C. to the reflux temperature, butif necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0503] (b) Protection of the compound of formula 8-2 may be carried outaccording to a number of standard procedures known to those skilled inthe art (e.g., “Protection of Phenols”, in Protective Groups in OrganicSynthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wileyand Sons, Inc. 1991, pp. 143-174).

[0504] (c) Preparation of the compound of formula (Ia⁵) may be carriedout according to the conditions illustrated in Scheme 1 and 1b.

[0505] (d) Cleavage of the protecting group may be carried out by anumber of standard procedures known to those skilled in the art (e.g.,“Protection of Phenols”, in Protective Groups in Organic Synthesis, 2ndEdition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc.1991, pp. 143-174).

[0506] As depicted in Scheme 9, the compound of formula (Ia), wherein atleast one of Y¹, Y², Y³ and Y⁴ is C—SO₂NH₂, A is phenyl, B is ethyleneand W is R^(1a)—N (R^(1a) is H or C₁₋₄alkyl), (hereinafter representedby Formula (Ia⁸)) may be prepared from the compound of formula (Ia),wherein at least one of Y¹, Y², Y³ and Y⁴ is C—SO₂NHtBu, A is phenyl, Bis ethylene and W is R^(1a)—N (R^(1a) is H or C₁₋₄alkyl), (hereinafterrepresented by Formula (Ia⁷)). The compound of formula (Ia⁷) may beprepared by the methods illustrated in Scheme 1 and 1b. Cleavage of theprotecting group may be carried out by a number of standard proceduresknown to those skilled in the art (e.g., Quan, Mimi L.; Ellis,Christopher D.; Liauw, Ann Y.; Alexander, Richard S.; Knabb, Robert M.,et al., J. Med. Chem., 1999, 42, 2760-2773).

[0507] Reaction Scheme 10 illustrates a method for the preparation ofthe compound formula (Ia) wherein at least one of Y¹, Y², Y³ and Y⁴ isC—NHSO₂R¹⁰, A is phenyl, B is ethylene, R¹⁰ is C₁-C₄ alkyl, W isR^(1a)—N (R^(1a) is H or C₁₋₄alkyl), (hereinafter represented by Formula(Ia⁹)).

[0508] Compound (Ia⁹) may be prepared through the process comprising:

[0509] (a) reduction of a compound of formula 10-1 to give a compound offormula 10-2;

[0510] (b) sulfonylation of the amino group of the compound 10-2 to givea compound of formula 10-3; and

[0511] (c) formation of a compound of formula (Ia⁹);

[0512] Each reaction step is described more specifically as follows.

[0513] (a) The intermediate 10-1 may be prepared by the methodsillustrated in Scheme 1. Reduction of nitro group may be carried outaccording to the conditions illustrated in Scheme 1.

[0514] (b) Sulfonylation of the amino group of the compound 10-2 may becarried out by a number of standard procedures known to those skilled inthe art (e.g., “Protection for the Hydroxy Group and the Amino Group”,in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene andP. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 117-118,379-384).

[0515] (c) Formation of the sulfonylurea compound of formula (Ia⁹) maybe carried out according to the conditions illustrated in Scheme 1 and1b.

[0516] Reaction Scheme 11 illustrates a method for the preparation ofthe compound of formula (Ia) wherein at least one of Y¹, Y², Y³ and Y⁴is C—NHC(═O)N(R³)(R⁴), A is phenyl, B is ethylene and W is R^(1a)—N(R^(1a) is H or C₁₋₄alkyl), (hereinafter represented by Formula (Ia¹⁰)).Compound (Ia¹⁰) may be prepared through the process comprising:

[0517] (a) urea formation with a compound of formula 11-1(10-2) to givea compound of formula 11-2; and

[0518] (b) formation of a compound of formula (Ia¹⁰);

[0519] Each reaction step is described more specifically as follows.

[0520] (a) The intermediate 11-1(10-2) as obtained in Scheme 10, may betreated with an isocyanate or cyanic acid (usually its salts) accordingto known procedures (e.g., Satchell and Satchell, Chem. Soc. Rev., 1975,4, 231-250). More specifically, this reaction may be carried out in asuitable reaction inert solvent such as dichloromethane, THF, benzene ortoluene. Reaction temperatures are generally in the range of −100° C. to250° C., preferably in the range of 0° C. to the reflux temperature, butif necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0521] (c) Formation of the sulfonylurea compound of formula (Ia¹⁰) maybe carried out according to the conditions illustrated in Scheme 1 and1b.

[0522] Intermediate compound 12-2 may be prepared by the methodsillustrated in Scheme 12. Intermediate 12-1 may be prepared by themethods illustrated in Scheme 1 and Scheme 1b. The reduction may becarried out under known hydrogenation conditions such as in the presenceof a metal catalyst such as palladium catalysts or platinum catalysts ina reaction inert solvent such as methanol, ethanol, ethyl acetate orTHF. If desired, the reaction is carried out under acidic conditions inthe presence of an acid such as hydrogen chloride or acetic acid.Reaction temperatures are generally in the range of −100° C. to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed.

[0523] In addition, an intermediate compound 13-2 may be prepared by themethods illustrated in Scheme 13. Intermediate 13-1 may be prepared bythe methods illustrated in Scheme 1. The reduction may also be carriedout by the methods illustrated in Scheme 1.

[0524] An intermediate compound 14-3 may be prepared by the methodsillustrated in Scheme 14. Intermediate 14-1 may be prepared by themethods illustrated in Scheme 1. Reduction of nitro group may be carriedout according to the conditions illustrated in Scheme 1. Sulfonylationof the amino group of the compound 14-2 may be carried out by a numberof standard procedures known to those skilled in the art (e.g.,“Protection for the Hydroxy Group and the Amino Group”, in ProtectiveGroups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M.Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 117-118, 379-384).

[0525] Intermediate compounds 15-6 and 15-7 may be prepared by themethods illustrated in Scheme 15. A compound of formula 15-1 may betreated with aqueous ammonia. Reaction temperatures are generally in therange of −100° C. to 250° C., preferably in the range of 0° C. to thereflux temperature, but if necessary, lower or higher temperature can beemployed. Reaction times are, in general, from an hour to a week,preferably from 3 hours to 5 days, however shorter or longer reactiontimes, if necessary, can be employed. Thus, the obtained intermediate15-2 may be treated with 1,3-diketone compound of formula 15-3, whereinL¹, L² and L³ is independently selected from, but not limited to, halo,C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, nitro, cyano, C₁₋₄ alkoxy-C₁₋₄alkyl, acetyl, C₃₋₇cycloalkyl, or two adjacent L¹, L² and L³ groups may be joined togetherto form an alkylene chain having 3 or 4 members in which one or two(non-adjacent) carbon atoms may be replaced by oxygen atoms in thepresence of a base such as pyridine, piperadine, imidazole,N,N-dimethylaminopyridine, CH₃C(═O)ONa or NaH₂PO₄ and in the presence orabsence of an acid such as acetic acid, hydrochloric aid or boric acid.Suitable reaction inert solvent includes water, dioxane, DMSO, DMF,p-toluene or ethanol. Reaction temperatures are generally in the rangeof −100° C. to 250° C., preferably in the range of 0° C. to the refluxtemperature, but if necessary, lower or higher temperature can beemployed. Reaction times are, in general, from an hour to a month,preferably from 6 hours to 14 days, however shorter or longer reactiontimes, if necessary, can be employed. Compounds 15-4 and 15-5 asobtained above may be treated with halogenating agent such as POCl₃,SOCl₂ or Vilsmeier complex (e.g., Laue T.; Plagens A., Eds.; NAMEDORGANIC REACTIONS, Wiley & Sons: New York, 1998, pp 258-262) in thepresence or absence of a suitable reaction inert solvent such asdichloromethane, benzene or DMF to give compounds of formula 15-6 and/or15-7. Reaction temperatures are generally in the range of −100° C. to250° C. preferably in the range of 0° C. to the reflux temperature, butif necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 minute to a day, preferably from 20minutes to 5 hours, however shorter or longer reaction times, ifnecessary, can be employed.

[0526] Reaction Scheme 16 illustrates a method for the preparation ofthe compound of formula (I) wherein R¹ is NH₂, A is phenyl, B isethylene and W is NH (hereinafter represented by Formula (Ia¹¹)) andthat of the compound of formula (I), wherein R¹ is NHC(═O)R¹⁶(R¹⁶ isC₁₋₄ alkyl), A is phenyl, B is ethylene and W is NH (hereinafterrepresented by Formula (Ia¹²)) and that of the compound of formula (I),wherein R¹ is NHS(O)₂R¹⁶(R¹⁶ is C₁₋₄ alkyl), A is phenyl, B is ethyleneand W is NH (hereinafter represented by Formula (Ia¹³))

[0527] Compounds (Ia¹¹), (Ia¹²) and (Ia¹³) may be prepared through theprocess comprising:

[0528] (a) 2-amino-benzimidazole or 2-amino-imidazopyridine ringformation) with a compound of formula 16-1(2-7) to give the compound offormula (Ia¹¹);

[0529] (b) carbonylation of the compound of formula (Ia¹¹) to give thecompound of formula (Ia¹²); and

[0530] (c) sulfonylation of the compound of formula (Ia¹¹) to give thecompound of formula (Ia¹³).

[0531] Each reaction step is described more specifically as follows.

[0532] (a) The compound 16-1(2-7) can be cyclized to form abenzimidazole or a imidazopyridine ring by reaction with an appropriatecyclizing agent to give the compound of formula (Ia¹¹) in a reactioninert solvent. Suitable cyclizing agents include cyanogen halide (e.g.,cyanogen bromide), cyanamide, and guanidine-carbamate. Suitable solventsinclude tetrahydrofuran (TBF), methanol, ethanol, acetonitrile, water,dimethylformamide and the like. This reaction may be carried out atabout 0° C. to the reflux temperature of the reaction mixture,preferably at room temperature to the reflux temperature for about 1minute to 120 hours, preferably 10 minutes to 72 hours.

[0533] (b) The compound of formula (Ia¹¹) may be reacted with anacylating agent such as alkylcarbonyl halide, acid anhydride in thepresence of a base such as triethylamine or pyridine. Suitable reactioninert solvents include TBF, DMF or benzene. The reaction may be carriedout at about 0° C. to about reflux temperature for about 1 minute to 120hours, preferably 10 minutes to 48 hours.

[0534] (c) The compound of formula (Ia¹¹) may also be reacted with ansulfonylating agent such as alkylsulfonyl halide, sulfonic acidanhydride in the presence of a base such as triethylamine or pyridine.Suitable reaction inert solvents include dichloromethane, THF, DMF orbenzene. The reaction may be carried out at about 0° C. to about refluxtemperature for about 1 minute to 120 hours, preferably 10 minutes to 48hours.

[0535] Reaction Scheme 17 illustrates a method for the preparation ofthe compound of formula (I) wherein R¹ is R¹⁶NH (R¹⁶ is C₁₋₈ alkyl), Ais phenyl, B is ethylene and W is O or R^(1a)—N (R^(1a) is H orC₁₋₄alkyl) (hereinafter represented by Formula (Ia¹⁴)) and that of thecompound of formula (I), wherein R¹ is (R¹⁶)₂N (R¹⁶ is C₁₋₈ alkyl), A isphenyl, B is ethylene and W is O or R^(1a)—N (R^(1a) is H or C₁₋₄alkyl)(hereinafter represented by Formula (Ia¹⁵)).

[0536] Compounds (Ia¹⁴) and (Ia¹⁵) may be prepared through the processcomprising:

[0537] (a) 2-amino-benzimidazole or 2-amino-imidazopyridine ringformation with a compound of formula 17-1 to give a compound of formula(Ia¹⁴); and

[0538] (b) alkylation of the compound of formula (Ia¹⁴) to give acompound of formula (Ia¹⁵).

[0539] Each reaction step is described more specifically as follows.

[0540] (a) A compound of formula 17-1 may be subjected to a reactionwith an isothiocyanate compound and a subsequent desulfurization underknown conditions to give the compound of formula (Ia¹⁴) (e.g., Y. Abe,H. Kayakiri, S. Satoh et al., J. Med. Chem. 1998, 41, 4062). Forexample, the first reaction may be carried out in a reaction inertsolvent such as THF, acetonitrile or an alcohol (e.g., ethanol) at fromabout room temperature to about 100° C. from about 30 minutes to 48hours. The cyclization may be carried out in the presence of an alkylhalide at from about 0° C. to reflux temperature from about 30 minutesto 48 hours.

[0541] (b) The compound of formula Ia¹⁴ may be treated with appropriatealkyl halides in the presence of a base such as lithium diisopropylamide (LDA), sodium hydride (NaH) or potassium t-butoxide in a reactioninert solvent such as hexamthylphosphorous triamide(HMPT), THF or DMF atabout 0° C. to about 100° C. for about 5 minutes to about 48 hours.

[0542] Reaction Scheme 18 illustrates a method for the preparation ofthe compound of formula (I) wherein R¹ is R¹⁸S (R¹⁸ is C₁₋₈ alkyl), A isphenyl, B is ethylene and W is O or R^(1a)—N (R^(1a) is H or C₁₋₄alkyl)(hereinafter represented by Formula (Ia¹⁷)). Compound (Ia¹⁷) may beprepared through the process comprising:

[0543] (a) 2-amino-benzimidazole or 2-amino-imidazopyridine ringformation with a compound of formula 18-1 to give a compound of formula(Ia¹⁶); and

[0544] (b) alkylation of the compound of formula (Ia¹⁶) to give acompound of formula (Ia¹⁷).

[0545] Each reaction step is described more specifically as follows.

[0546] (a) The compound of formula 18-1 may be subjected to a reactionwith an thiocarbonyl reagent such as 1,1-thiocarbonylimidazole ordi(2-pyridyl)thionocarbonate to give the compound of formula (Ia¹⁶)(e.g., Y. Abe, H. Kayakiri, S. Satoh et al., J. Med. Chem. 1998, 41,4062). For example, the reaction may be carried out in a reaction inertsolvent such as THF, acetonitrile, dichloromethane or an alcohol (e.g.,ethanol) at from about room temperature to about 100° C. from about 30minutes to 48 hours. The cyclization may be carried out in the presenceof an alkyl halide at from about 0° C. to reflux temperature from about30 minutes to 48 hours.

[0547] (b) The compound of formula (Ia¹⁶) may be treated withappropriate alkyl halides in the presence of a base such as potassiumcarbonate, lithium diisopropyl amide (LDA), sodium hydride (NaH) orpotassium t-butoxide in a reaction inert solvent such ashexamthylphosphorous triamide (HMPT), THF or DMF at about 0° C. to about100° C. for about 5 minutes to about 48 hours.

[0548] As shown in Scheme 19, the compound of formula 19-3 (1-5) mayalso be prepared by reacting a compound of formula 19-1 with asubstituted benzene compound of formula 19-2 to give a1-phenylbenzimidazole compound of formula 19-3;

[0549] The compounds of formula 19-1 may be synthesized by any of theknown methods. The group G¹⁹ of the compounds of formula 19-2 is aselected from a suitable displaceable group, for example, fluoro,chloro, bromo, iodo, trifluoromethanesulfonyloxy, methanesulfonyloxy,p-toluenesulfonyloxy, or boronic acid group.

[0550] The coupling reaction may be carried out in the presence of abase in a reaction inert solvent. A preferred base is selected from, forexample, but not limited to, an alkali or alkaline earth metalhydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide,potassium hydroxide, sodium methoxide, sodium ethoxide, potassiumtert-butoxide, sodium carbonate, potassium carbonate, sodium hydride orpotassium hydride, or an amine such as triethylamine, tributylamine,diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine.Preferred reaction inert solvents include, but are not limited to,benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine,dichloromethane, 1,2-dichloroethane, tetrahyrofuran, acetonitrile,dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO),1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone or mixturesthereof. Reaction temperatures are generally in the range of −100 to250° C., preferably in the range of 0 to 150° C., but if necessary,lower or higher temperature can be employed. Reaction times are, ingeneral, from 1 minute to several weeks, preferably from 20 minutes to 1week, however shorter or longer reaction times, if necessary, can beemployed. Conveniently, the compound of formula 19-1 may be reacted withthe compound of formula 19-2 in the presence of a suitable catalyst toform the compound of formula 19-3 by any synthetic procedure applicableto structure-related compounds known to those skilled in the literature(e.g., Lam, P. Y. S.; Clark, C. G.; Saubern, S; Adams, J; Winters, M.P.; Chan, D. M. T.; Combs, A., Tetrahedron Lett., 1998, 39, 2941-2944.,Kiyomori, A.; Marcoux, J.; Buchwald, S. L., Tetrahedron Lett., 1999, 40,2657-2660., Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M.Y.; DeShong, P.; Clark, C. G., J. Am. Chem. Soc., 2000, 122, 7600-7601.,Collman, J. P.; Zhong, M., Org. Lett., 2000, 2, 1233-1236.). Preferredreaction catalyst is selected from, for example, but not limited to,tetrakis(triphenylphosphine)-palladium,bis(triphenylphosphine)palladium(II) chloride, copper(0), copper(I)acetate, copper(I) bromide, copper(I) chloride, copper(I) iodide,copper(I) oxide, copper(I) trifluoromethanesulfonate, copper(I) acetate,copper(II) bromide, copper(II) chloride, copper(II) iodide, copper(II)oxide, or copper(II) trifluoromethanesulfonate.

[0551] As shown in Scheme 20, the compound of formula 1-5 or 1e-4 mayalso be prepared through the process comprising:

[0552] (a) acylation of a compound of formula 20-1;

[0553] (b) benzimidazole or imidazopyridine ring cyclization of acompound of formula 20-2 to give a compound of formula 20-3.

[0554] Each reaction step is described more specifically as follows.

[0555] (a) A compound of formula 20-1 (1-3 or 1e-3) is reacted with anappropriate acylating reagent to give a compound of formula 20-2 in areaction inert solvent in the presence of, or absence of a couplingreagent and/or additive. Suitable acylating reagents include, but arenot limited to, a carboxylic acid, an amino carboxylic acid, an acidanhydride (e.g., acetic anhydride, isobutyric anhydride, benzoicanhydride, isonicotinic anhydride and the like) a formamidine (e.g.,formamidine alkylate such as formamidine acetate), an alkyl carbonylhalide (e.g., a cycloalkyl carbonyl halide, bicyclic, heterocyclic, orbicyclic-heterocyclic-carbonyl halide, spirocarbocyclic- orspiro-heterocyclic-carbonyl halide), an aryl or an aryl alkyl carbonylhalide (e.g., phenylacethyl halide), an heteroaryl carboxylic acid(e.g., a piperidinyl carboxylic acid compound), trialkyl orthoformate(e.g., triethyl orthoformate), and the like. Suitable reaction inertsolvents include, but are not limited to, benzene, toluene, xylene,o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane,tetrahyrofuran (THF), dimethylformamide (DMF), 1,4-dioxane,dimethylsulfoxide (DMSO) or mixtures thereof. Suitable coupling reagentsare those typically used in peptide synthesis including, but are notlimited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide(DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC),benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP), diphenylphosphorylazide (DPPA),N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminiumhexafluorophosphate (HBTU), tetramethylfluoroformamidiniumhexafluorophosphate (TFFH), bromo[tri(1-pyrrolidinyl)]phosphoniumhexafluorophosphate (PyBroP), bis(2-oxo-1,3-oxazolidin-3-yl)phosphinicchloride (BOP-Cl),(1H-1,2,3-benzotriazol-1-yl-oxy)[tri(1-pyrrolidinyl)]phosphoniumhexafluorophosphate (PyBOP), or the like. Suitable additives include,but are not limited to, 1H-1,2,3-benzotriazol-1-ol (HOBt),3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt),N,N-dimethyl-4-pyridinamine (DMAP), or the like. The reaction may becarried out at a temperature in the range from of −100° C. to 250° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a few days, preferably from 30 minutesto 48 hours, however shorter or longer reaction times, if necessary, canbe employed.

[0556] (b) The resulting amide compound of formula 20-2 may also becyclized to form a benzimidazole or imidazopyridine ring in the presenceof a base (Bashir, M.; Kingston, D. G. I.; Carman, R. J.; Van Tassell,R. L.; Wilkins, T. D., Heterocycles, 1987, 26, 2877-2886.). A preferredbase is selected from, for example, but not limited to, an alkali oralkaline earth metal hydroxide, alkoxide, or carbonate, such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide,sodium ethoxide, potassium tert-butoxide, sodium carbonate, or potassiumcarbonate, in a reaction inert solvent. Preferred reaction inertsolvents include, but are not limited to, water, methanol, ethanol,tetrahyrofuran (THF), benzene, toluene, xylene, dichloromethane,ethyleneglycol, or mixtures thereof. Reaction temperatures are generallyin the range of −100 to 250° C., preferably in the range of 0 to 70° C.,but if necessary, lower or higher temperature can be employed. Reactiontimes are, in general, from 1 hour to 5 days, preferably from 3 hours to2 days, however shorter or longer reaction times, if necessary, can beemployed.

[0557] As shown in Scheme 21, an intermediate compound of formula 21-2(1-4 or 1e-4) may also be prepared.

[0558] The compound of formula 21-1 may be reacted with an appropriatealdehyde in a reaction inert solvent in the presence of, or absence ofacid to produce an intermediate Shiff base. Succeedingly, the Shiff basecan be oxidativery cyclized to form a benzimidazole or imidazopyridinering by iodine, sulfur, cupric acetate, mercuric oxide, chloranil,active manganese dioxide, lead tetraacetate, nickel peroxide, bariumpermanganate, or the like. Suitable reaction inert solvents include, butare not limited to, methanol, ethanol, water, benzene, toluene, xylene,mesitylene, o-dichlorobenzene, nitrobenzene, dichloromethane,1,2-dichloroethane, tetrahyrofuran (THF), dimethoxyethane (DME),1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. The reactionmay be carried out at a temperature in the range from of −100 to 250°C., preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timesare, in general, from 1 minute to a few days, preferably from 30 minutesto 48 hours, however shorter or longer reaction times, if necessary, canbe employed.

[0559] Also, the aryl or heteroaryl fused imidazole comopounds ofFormula (II) of this invention may be prepared by a variety of syntheticmethods known to those skilled in the art.

[0560] Reaction Scheme 22 illustrates a method for the preparation ofthe compound of formula (II).

[0561] The compound of formula (II) may be prepared from the compound of22-1(1-1) according to the similar procedure to that of described inScheme 1.

[0562] Also, the aryl or heteroaryl comopounds of Formula (III) of thisinvention may be prepared by a variety of synthetic methods known tothose skilled in the art.

[0563] Reaction Scheme 23 illustrates a method for the preparation ofthe compound of formula (II).

[0564] The compound of formula (III) may be prepared from the compoundof 23-1(22-3) according to the similar procedure to that of described inScheme 20.

[0565] In addition, the benzimidazole moiety of the compound of formula(I) which can be used herein may be prepared by known methods as shownin, for example: (1) Grimmett, M. R. Imidazoles and Their BenzoDerivatives: (iii) Synthesis and Applications. In ComprehensiveHeterocyclic Chemistry, Kevin T. Potts, Eds.; Pergamon Press Ltd.:Oxford, UK, 1984; Vol.5, pp457-498; (2) Grimmett, M. R. Imidazoles. InComprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds.; ElsevierScience Ltd.: Oxford, UK, 1996; Vol.3, pp77-220.

[0566] The imidazopyridine moiety of the compound of formula (I) whichcan be used herein may be prepared by known methods as shown in, forexample: Townsend L. B; Wise D. S. Bicyclo 5-6 Systems: ThreeHeteroatoms 2:1. In Comprehensive Heterocyclic Chemistry II, ChristopherA. Ramsden, Eds.; Elsevier Science Ltd.: Oxford, UK, 1996; Vol.7,pp283-349.

[0567] The starting materials 1-1, 1-8, 1-9, 1a-2, 1d-3, 1d-4, 1d-5,1d-6, 1f-0, 2-2, 5-4, 15-1, 15-3, 22-0 and the other reactants are knownor commercially available compounds, or may be prepared according toknown procedures for a person skilled in the art.

[0568] The subject invention also includes isotopically-labelledcompounds, which are identical to those recited in formula (I), but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassay. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of presentation and detectability.Further, substitution with heavier isotopes such as deutrium, i.e., ²H,can afford therapeutic advantage resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirement and, hence, may be preferred in some circumstances.Isotopically labelled compounds of formula (I) of this invention andprodrugs thereof can generally be prepared by carrying out the proceduredisclosed in above-disclosed Schemes and/or Examples and Preparationsbelow, by submitting a readily available isotopically labelled reagentfor a non-isotopically labelld reagent.

[0569] The present invention includes salt forms of the compounds (I) asobtained Certain compounds of the present invention are capable offorming pharmaceutically acceptable non-toxic cations. Pharmaceuticallyacceptable non-toxic cations of compounds of formula (I) may be preparedby conventional techniques by, for example, contacting said compoundwith a stoichiometric amount of an appropriate alkali or alkaline earthmetal (sodium, potassium, calcium and magnesium) hydroxide or alkoxidein water or an appropriate organic solvent such as ethanol, isopropanol,mixtures thereof, or the like.

[0570] The bases which are used to prepare the pharmaceuticallyacceptable base addition salts of the acidic compounds of this inventionof formula (I) are those which form non-toxic base addition salts, i.e.,salts containing pharmaceutically acceptable cations, such as adenine,arginine, cytosine, lysine, benethamine(i.e.,N-benzyl-2-phenyletylamine), benzathine(i.e.,N,N-dibenzylethylenediamine), choline, diolamine(i.e., diethanolamine),ethylenediamine, glucosamine, glycine, guanidine, guanine,meglurnine(i.e., N-methylglucamine), nicotinamide, olamine(i.e.,ethanolamnine), ornithine, procaine, proline, pyridoxine, serine,tyrosine, valine and tromethamine(i.e., tris ortris(hydroxymethyl)aminomethane). The base addition salts can beprepared by conventional procedures.

[0571] Insofar as the certain compounds of this invention are basiccompounds, they are capable of forming a wide variety of different saltswith various inorganic and organic acids.

[0572] The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the basic compounds of this inventionof formula (I) are those which form non-toxic acid addition salts, i.e.,salts containing pharmaceutically acceptable anions, such as thechloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbi-tartrate, succinate, malate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, adipate, aspartate camsylate, (i.e.,1,2-ethanedisulfontate), estolate(i.e., laurylsulfate), gluceptate(i.e.,gluscoheptonate), gluconate, 3-hydroxy-2-naphthoate, xionofoate(i.e.,1-hydrroxy-2-naphthoate), isethionate,(i.e., 2-hydroxyethanesulfonate),mucate(i.e., galactarate), 2-naphsylate(i.e., naphthalenesulphonate,stearate, cholate, glucuronate, glutamate, hippurate, lactobionate,lysinate, maleate, mandelate, napadisylate, nicatinate,polygalacturonate, salicylate, sulphosalicylate, tannate, tryptophanate,borate, carbonate, oleate, phthalate and pamoate (i.e.,1.1′-methylene-bis-(2-hydroxy-3-naphthoate). The acid addition salts canbe prepared by conventional procedures.

[0573] Also included within the scope of this invention arebioprecursors (also called pro-drugs) of the compounds of the formula(I). A bioprecursor of a compound of the formula (I) is a chemicalderivative thereof which is readily converted back into the parentcompound of the formula (I) in biological systems. In particular, abioprecursor of a compound of the formula (I) is converted back to theparent compound of the formula (I) after the bioprecursor has beenadministered to, and absorbed by, a mammalian subject, e.g., a humansubject. For example, it is possible to make a bioprecursor of thecompounds of formula (I) in which one or both of L and W includeshydroxy groups by making an ester of the hydroxy group. When only one ofL and W includes hydroxy group, only mono-ester are possible. When bothL and W include hydroxy, mono- and di-esters (which can be the same ordifferent) can be made. Typical esters are simple alkanoate esters, suchas acetate, propionate, butyrate, etc. In addition, when L or W includea hydroxy group, bioprecursors can be made by converting the hydroxygroup to an acyloxymethyl derivative (e.g., a pivaloyloxymethylderivative) by reaction with an acyloxymethyl halide (e.g.,pivaloyloxymethyl chloride).

[0574] When the compounds of the formula (I) of this invention may formsolvates such as hydrates, such solvates are included within the scopeof this invention.

[0575] Also, the compounds of formula (I) may be expected more effectivetherapeutic effects with being co-administered with a COX-2 selectiveNSAID.

[0576] Further, the present invention also encompasses a pharmaceuticalcomposition for the treatment of inflammation, rheumatoid arthritis,pain, common cold, osteoarthritis, neuropathic pain, brain tumor,diuresis, or the like, which comprises a therapeutically effectiveamount of the aryl or heteroaryl fused imidazole compound of formula (I)and a COX-2 selective NSAID or their pharmaceutically acceptable salttogether with a pharmaceutically acceptable carrier.

[0577] The compounds of the invention may advantageously be employed incombination with one or more other therapeutic ingredients selectedfrom, a COX-2 selective, COX-1 selective or non-selective NSAIDs,opioids, anticonvulsants, antidepressants, local anesthetics,disease-modifying anti-rheumatoid drugs, or steroid.

[0578] The combination with a COX-2 selective NSAID is particularlyfavorured for use in the prophylaxis and treatment of pain andarthritis. Examples of a COX-2 selective NSAID are nimesulide,celecoxib, rofecoxib and valdecoxib.

[0579] The compounds of Formula (I) have been found to possess anactivity as prostaglandin E₂ receptor antagonist, preferably as EP₄receptor antagonist. Preferably, these compounds are useful as ananalgesic, anti-inflammatory, diuretic, and the like, in mammaliansubjects, especially humans in need of such agents. The affinity,antagonist activities and analgesic activity can be demonstrated by thefollowing tests respectively.

Method for Assessing Biological Activities In vitro Assays

[0580] Rat EP Receptor Cell Membrane Binding Assay:

[0581] Stable Expression of Rat EP1, 2, 3 and 4 Receptors in the HumanEmbryonic Kidney (HEK293) Cell Line

[0582] The cDNA clones of rat EP1, 2, 3 and 4 receptors are obtained bypolymerase chain reaction (PCR) from rat kidney or heart cDNA libraries(Clontech). Human embryonic kidney cells (HEK 293) are stablytransfected with expression vectors for rat EP, 2, 3 and 4 receptors inaccording to the method described in the article; the journal ofbiological chemistry vol.271 No.39, pp23642-23645.

[0583] Preparation of membrane fraction:

[0584] The EP1, 2, 3 and 4 transfectant are grown in Dulbecco's modifiedEagle's medium containing 10% fetal calf serum, 100 U/ml penicillin, 100μg/ml streptomycin and 600 μg/ml G418 (selection medium) at 37° C. in ahumidified atmosphere of 5% CO₂ in air. For the membrane preparation,cells are harvested with phosphate buffered saline (PBS) and centrifugedat 400×g for 5 min. The pellet is suspended with child (4° C.) PBScontaining 1 mM Pefabloc (4-(2-aminoethyl)-benzenesulfonyl fluoride(AEBSF)), 10 μM Phosphoramidon, 1 μM Pepstatin A, 10 μM Elastatinal, 100μM Antipain. Cells are lysed with ultrasonic cell disrupter for 20-secsonication. Then cell mixtures are centrifuged at 45,000×g for 30minutes. The pellet is resuspended in assay buffer (10 mM2-morpholinoeth-anesulfonic acid (MES)-KOH, 1 mM etylenediaminetetra-acetic acid (EDTA), 10 mM MgCl₂, pH 6.0), and proteinconcentration is determined by Bradford method (Bio-Rad assay). Thismembrane preparation is stored at −80° C. freezer until use for bindingassay.

[0585] Binding Assay:

[0586] Membrane Binding Assay

[0587] [³H]-PGE₂ membrane binding assays are performed in the reactionmixture of 10 mM MES/KOH (pH6.0), 10 mM MgCl₂, 1 mM EDTA, 1 nM [³H]-PGE₂(Amersham TRK431, 164Ci/mmol), 2˜10 μg of protein from membrane fraction(rat EP1, 2, 3 and 4/HEK293 transfectant) and test compound (totalvolume is 0.1 ml in 96 well polypropylene plate). Incubation isconducted for 60 min at room temperature prior to separation of thebound and free radioligand by rapid filtration through glass fiberfilters (Printed Filtermat B, 1205-404, glass fiber, double thickness,size 102×258 mm, Wallac inc., presoaked in 0.2% polyethylenimine).Filters are washed with assay buffer and the residual [³H]-PGE₂ bound tothe filter is determined by liquid scintillation counter (1205Betaplate™). Specific binding is defined as the difference between totalbinding and nonspecific binding which is determined in the presence of10 μM PGE₂.

[0588] cAMP Assay in Rat EP₄ Transfectant

[0589] HEK293 cells expressing rat EP₄ receptors (rEP₄ cells) aremaintained in DMEM containing 10% FCS and 600 μg/ml geneticin. Forharvesting rEP₄ cells, culture medium is aspirated and cells in 75 cm²flask are washed with 10 ml of phosphate buffered saline (PBS). Another10 ml of PBS is added to the cells and incubated for 20 min at roomtemperature. Rat EP₄ cells are harvested by pipetting and centrifuged at300 g for 4 min. Cells are resuspended in DMEM without neutral red at adensity of 5×10⁵ cells/ml. The cells (70 μl) are mixed with 70 μl ofDMEM (without neutral red) containing 2 mM IBMX (PDE inhibitor), 1 nMPGE₂ and test compounds in PCR-tubes, and incubated at 37° C. for 10min. The reaction is stopped by heating at 100° C. for 10 min withthermal cycler. Concentration of cAMP in reaction mixtures is determinedwith SPA cAMP Kit (Amersham) according to the manufacture's instruction.

[0590] Reference: Eur.J.Pharmacol. 340 (1997) 227-241

In vivo Assays

[0591] Carrageenan Induced Mechanical Hyperalgesia in Rats:

[0592] Male 4-week-old SD rats (Japan SLC) were fasted over night.Hyperalgesia was induced by intraplantar injection of λ-carrageenin (0.1ml of 1% w/v suspension in saline, Zushikagaku). The test compounds (1ml of 0.1% methylcellulose/100 g body weight) were given per orally at5.5 hours after the carrageenin injection. The mechanical pain thresholdwas measured by analgesy meter (Ugo Basile) at 4, 5, 6.5 and 7.5 hoursafter the carrageenin injection and the change of pain threshold wascalculated.

[0593] Reference: Randall L. O. & Selitto I. J., Arch. Int. Pharmacodyn.111, 409-419, 1957

[0594] Prostaglandin E₂(PGE₂)-induced Thermal Hyperalgesia in Rats:

[0595] Male 4-week-old SD rats (Japan SLC) were fasted over night.Hyperalgesia was induced by intraplantar injection of 100 ng of PGE2 in5% DMSO/saline(100 ul) into the right hindpaw of the rats. Animals weregiven orally or intravenously either vehicle (po: 0.1% methyl cellulose,iv: 10% DMSO/saline) or a test compound 15 or 5 min. prior to PGE₂injection, respectively. Rats were placed in plastic cages of plantartest apparatus (Ugo Basile) and the mobile radiant heat source wasfocused on right hind paw of the rats. The thermal paw-withdrawallatency (sec.) was measured at 15 min after PGE₂ injection and thechange in withdrawal threshold was calculated. Reference: Hargreaves K.et al., Pain 32, 77-88, 1988.

[0596] Most of the compounds prepared in the working examples appearinghereafter demonstrate higher affinity for EP₄-receptors than for EP1, 2and 3-receptors.

[0597] Some preferred compounds prepared in the working examples asdescribed below were tested by the above method, and showed an ED₅₀value under 60 mg/kg.

[0598] The aryl or heteroaryl fused imidazole compounds of formula (I)of this invention can be administered via either the oral, parenteral ortopical routes to mammals. In general, these compounds are mostdesirably administered to humans in doses ranging from 0.1 mg to 3000mg, preferably from 1 mg to 500 mg, which may be administered in asingle dose or in divided doses throughout the day, although variationswill necessarily occur depending upon the weight and condition of thesubject being treated, the disease state being treated and theparticular route of administration chosen. However, for example, adosage level that is in the range of from 0.01 mg to 10 mg per kg ofbody weight per day is most desirably employed for treatment of painassociated with inflammation.

[0599] The compounds of the present invention may be administered aloneor in combination with pharmaceutically acceptable carriers or diluentsby either of the above routes previously indicated, and suchadministration can be carried out in single or multiple doses. Moreparticularly, the novel therapeutic agents of the invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically acceptable inert carriers inthe form of tablets, capsules, lozenges, troches, hard candies, powders,sprays, creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various nontoxic organic solvents, etc. Moreover,oralpharmaceutical compositions can be suitably sweetened and/orflavored. In general, the therapeutically-effective compounds of thisinvention are present in such dosage forms at concentration levelsranging 5% to 95% by weight.

[0600] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dipotassium phosphate and glycine may be employed along with variousdisintegrants such as starch and preferably corn, potato or tapiocastarch, alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatin capsules; preferred materials in this connection alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof.

[0601] For parenteral administration, solutions of a compound of thepresent invention in either sesame or peanut oil or in aqueous propyleneglycol may be employed. The aqueous solutions should be suitablybuffered (preferably pH>8) if necessary and the liquid diluent firstrendered isotonic. These aqueous solutions are suitable for intravenousinjection purposes. The oily solutions are suitable for intra-articular,intra-muscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well known to those skilled in theart. Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, ointments and the like, in accordance with standardpharmaceutical practice.

EXAMPLES

[0602] The invention is illustrated in the following non-limitingexamples in which, unless stated otherwise: all operations were carriedout at room or ambient temperature, that is, in the range of 18-25° C.;evaporation of solvent was carried out using a rotary evaporator underreduced pressure with a bath temperature of up to 60° C.; reactions weremonitored by thin layer chromatography (TLC) and reaction times aregiven for illustration only; melting points (mp) given are uncorrected(polymorphism may result in different melting points); the structure andpurity of all isolated compounds were assured by at least one of thefollowing techniques: TLC (Merck silica gel 60 F₂₅₄ precoated TLCplates), mass spectrometry, nuclear magnetic resonance (NMR), infraredred absorption spectra (IR) or microanalysis. Yields are given forillustrative purposes only. Flash column chromatography was carried outusing Merck silica gel 60 (230-400 mesh ASTM). Low-resolution massspectral data (EI) were obtained on a Automass 120 (JEOL) massspectrometer. Low-resolution mass spectral data (ESI) were obtained on aQuattro II (Micromass) mass spectrometer or a ZMD (Micromass). NMR datawas determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz(JEOL JNM-LA300 spectrometer) using deuterated chloroform (99.8% D) ordimethylsulfoxide (99.9% D) as solvent unless indicated otherwise,relative to tetramethylsilane (TMS) as internal standard in parts permillion (ppm); conventional abbreviations used are: s=singlet,d=doublet, t=triplet, q=quartet, quint=quintet, m=multiplet, br.=broad,etc. IR spectra were measured by a Shimazu infrared spectrometer(IR-470). Chemical symbols have their usual meanings; bp (boilingpoint), mp (melting point), L (liter(s)), mL (milliliter(s)), g(gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles), eq.(equivalent(s)), quant. (quantitative yield).

Example 12-Ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyrdine

[0603] Step 1. 4,6-Dimethyl-3-nitro-2(1H)-pyridinone

[0604] A mixture of ethyl nitroacetate (80.0 g, 601 mmol) in ammoniumhydroxide (25% NH₃ in water, 400 mL) was stirred at room temperature for3 days, and then the solution was concentrated by air-drying. Theresidue was dissolved in water (450 mL). To the solution was added2,4-pentanedione (73.1 g, 730 mmol), pyridine (16.2 mL, 200 mmol) andacetic acid (11.4 mL, 200 mmol), and the mixture was stirred for anadditional 7 days. The resulting precipitates were collected byfiltration and dried under reduced pressure to give 35.0 g (35%) of thetitle compound as yellow solids: ¹H-NMR (DMSO-D₆) δ 12.44 (1H, br. s),6.06 (1H, s), 2.19 (3H, s), 2.13 (3H, s).

[0605] Step 2. 2-Chloro-4,6-dimethyl-3-nitropyridine

[0606] A mixture of 4,6-dimethyl-3-nitro-2(1H)-pyridinone (step 1, 10.0g, 29.7 mmol) in phosphorus oxychloride (35 mL, 187.3 mmol) was stirredat 95° C. for 3 h, then cooled to 45° C. The excess amount of phosphorusoxychloride was removed by distillation under reduced pressure at 45° C.The residue was cooled to room temperature, and diluted withdichloromethane (75 mL). The resulting solution was cooled to 0° C., and2N hydrochloric acid (50 mL) was added dropwise into the solution. Theorganic layer was separated, and washed with 2N hydrochloric acid (4×25mL), 2N aqueous NaOH (2×50 mL) and brine (50 mL). The organic phase wasdried (MgSO₄) and concentrated under reduced pressure to give 10.0 g(90%) of the title compound as white solids: ¹H-NMR (CDCl₃) δ 7.07 (1H,s), 2.56 (3H, s), 2.35 (3H, s).

[0607] Step 3.2-{4-[(4,6-Dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

[0608] A mixture of 2-chloro-4,6-dimethyl-3-nitropyridine (step 2, 1.3g, 7.0 mmol) and 4-aminophenylethyl alcohol (1.4 g, 10.2 mmol) wasplaced in a sealed tube and heated at 150° C. for 3 h. The reactionmixture was cooled and purified by flash column chromatography on silicagel eluting with hexane/ethyl acetate (2:1) to afford 1.6 g (80%) of thetitle compound as orange solids: ¹H-NMR (CDCl₃) δ 9.55 (1H, br. s), 7.57(2H, d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz), 6.52 (1H, s), 3.84 (2H, t,J=6.4 Hz), 2.85 (2H, t, J=6.4 Hz), 2.54 (3H, s), 2.42 (3H, s).

[0609] Step 4.2-{4-[(3-Amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol

[0610] To a stirred solution of2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 3,1.6 g, 5.6 mmol) in ethyl acetate (15 mL) was added 10% Pd—C (160 mg).The mixture was stirred at room temperature for 6 h under hydrogenatmosphere. The palladium catalyst was removed by filtration and washedwith ethanol (100 mL). The filtrate was concentrated under reducedpressure to afford 1.3 g (92%) of the title compound as pale yellowsolids: ¹H-NMR (CDCl₃) δ 7.10 (4H, s), 6.61 (1H, s), 3.81 (2H, t, J=6.4Hz), 2.80 (2H, t, J=6.4 Hz), 2.36 (3H, s), 2.19 (3H, s).

[0611] Step 5.2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[0612] To a stirred suspension of2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4,1.3 g, 5.1 mmol) in toluene (30 mL) was added dropwise propionylchloride (990 mg, 10.7 mmol) at 0° C., and the reaction mixture washeated at reflux temperature for 2 h. After cooling, the mixture waspoured into water (50 mL) and extracted with ethyl acetate (100 mL). Theorganic layer was washed with 2N aqueous NaOH (50 mL) and brine (50 mL),then dried (MgSO₄). Removal of solvent gave 1.8 g (quant.) of the titlecompound as brown solids: ¹H-NMR (CDCl₃) δ 7.41 (2H, d, J=8.4 Hz), 7.33(2H, d, J=8.4 Hz), 6.90 (1H, s), 4.37 (2H, t, J=6.9 Hz), 3.04 (2H, t,J=6.9 Hz), 2.82 (2H, q, J=7.6 Hz), 2.65 (3H, s), 2.52 (3H, s), 2.35 (2H,q, J=7.6 Hz), 1.27 (3H, t, J=7.6 Hz), 1.14 (3H, t, J=7.6 Hz).

[0613] Step 6.2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0614] To a solution of2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 5, 1.75 g, 5.1 mmol) in methanol/THF (v/v, 1:1, 28 mL)was added 4N aqueous LiOH (4.6 mL, 18.4 mmol) and the resulting mixturewas stirred at room temperature. After 3 h, the mixture wasconcentrated. The residue was dissolved in water (30 mL) and extractedwith ethyl acetate (100 mL). The organic layer was washed with brine (50mL), dried (MgSO₄), and concentrated. Purification by flash columnchromatography on silica gel eluting with hexane/ethyl acetate (gradientelution from 2:1 to 0:1) to afford 1.3 g (86%) of the title compound aspale brown solids: ¹H-NMR (CDCl₃) δ 7.40 (2H, d, J=8.4 Hz), 7.31 (2H, d,J=8.4 Hz), 6.91 (1H, s), 3.81-3.75 (2H, m), 3.47 (1H. br. s), 2.92 (2H,t, J=6.9 Hz), 2.81 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.51 (3H, s), 1.27(3H, t, J=7.6 Hz).

[0615] Step 7.3-[4-(2-Chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0616] To a solution of2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 6, 2.2 g, 7.4 mmol) in toluene (40 mL) was added thionyl chloride(2.0 mL, 23.6 mmol), and the resulting mixture was stirred at 80° C. for3 h. The volatile components were removed under reduced pressure, andthe residue was purified by flash column chromatography on silica geleluting with hexane/ethyl acetate (gradient elution from 2:1 to 1:1) toafford 2.1 g (90%) of the title compound as white solids: ¹H-NMR (CDCl₃)δ 7.41 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 6.90 (1H, s), 3.78(2H, t, J=7.4 Hz), 3.15 (2H, t, J=7.4 Hz), 2.83 (2H, q, J=7.6 Hz), 2.71(3H, s), 2.54 (3H, s), 1.28 (3H, t, J=7.6 Hz).

[0617] Step 8.2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide

[0618] To a stirred solution of3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 7, 2.8 g, 9.0 mmol) and KI (1.5 g, 9.0 mmol) in DMF (50 mL) wasadded sodium azide (1.2 g, 18.0 mmol), and then the resulting mixturewas stirred overnight at 100° C. The reaction mixture was poured intowater (100 mL), and extracted with ethyl acetate (100 mL). The organiclayer was washed with water (50 mL) and brine (50 mL), then dried(Na₂SO₄). After removal of solvent, the crude product was purified byflash column chromatography on silica gel eluting with hexane/ethylacetate (1:1) to afford 2.35 g (85%) of the title compound as whitesolids:

[0619]¹H-NMR (CDCl₃) δ 7.41 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz),6.90 (1H, s), 3.59 (2H, t, J=7.1 Hz), 2.99 (2H, t, J=7.1 Hz), 2.83 (2H,q, J=7.6 Hz), 2.65 (3H, s), 2.52 (3H, s), 1.27 (3H, t, J=7.6 Hz).

[0620] Step 9.2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0621] To a solution of2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide (step 8, 2.35 g, 7.3 mmol) in methanol (50 nmL) was added 10% Pd—C(200 mg). The resulting mixture was stirred for 4 h under hydrogenatmosphere. The mixture was filtered through a pad of Celite and thefiltrate was concentrated. The residue was purified by flash columnchromatography on silica gel eluting withdichloromethane/methanol/triethylamine (100:5:1) to afford 2.01 g (94%)of the title compound as white solids: ¹H-NMR (CDCl₃) δ 7.39 (2H, d,J=8.4 Hz), 7.32 (2H, d, J=8.4 Hz), 6.90 (1H, s), 3.05 (2H, t, J=7.3 Hz),2.88-2.78 (4H, m), 2.65 (3H, s), 2.51 (3H, s), 1.28 (3H, t, J=7.6 Hz).

[0622] Step 10.2-Ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4.5-b]pyridine

[0623] To a solution of2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 9, 1.2 g, 4.0 mmol) in dichloromethane (15 mL) was addedp-toluenesulfonyl isocyanate (805 mg, 4.0 mmol). The resulting mixturewas stirred at room temperature for 3 h. After removal of solvent, theresidue was purified by flash column chromatography on silica geleluting with dichloromethane/methanol (20:1) to afford 1.10 g (56%) ofthe title compound as white solids: ¹H-NMR (CDCl₃) δ 7.85 (2H, d, J=8.2Hz), 7.32 (2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.4 Hz), 7.16 (2H, d, J=8.4Hz), 6.91 (1H, s), 6.12 (1H, br. s), 3.55-3.46 (2H, m), 2.85 (2H, t,J=6.3 Hz), 2.74-2.64 (5H, m), 2.42 (3H, s), 2.41 (3H, s), 1.21 (3H, t,J=7.6 Hz).

Example 22-Ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4.5-b]pyridine,sodium salt

[0624] To a solution of2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(Example 1, 5.0 g, 10.2 mmol) in methanol (20 mL) was added 2N aqueousNaOH (5.1 mL, 10.2 mmol). The resulting mixture was stirred at roomtemperature for 5 min and concentrated. The residual solids werecollected by filteration and dried under reduced pressure at 50° C. toafford the title compound as white solids: ¹H-NMR (DMSO-D₆) δ 7.60 (2H,d, J=8.2 Hz), 7.31-7.39 (4H, m), 7.14 (2H, d, J=8.2 Hz), 6.96 (1H, s),3.15 (2H, br. s), 2.66-2.75 (4H, m), 2.53 (3H, s), 2.40 (3H, s), 2.28(3H, s), 1.20 (3H, t, J=7.6 Hz).

Example 32-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[0625] To a solution of2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 6 of Example 1, 300 mg, 1.0 mmol) in dichloromethane (10 mL) wasadded p-toluenesulfonyl isocyanate (237 mg, 1.2 mmol). The resultingmixture was stirred at room temperature overnight. After removal ofsolvent, the residual solids were recrystallized from ethyl acetate toafford 454 mg (92%) of the title compound as white solids: ¹H-NMR(CDCl₃) δ 7.93 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.22 (4H, s),6.92 (1H, s), 4.87 (1H, br. s), 4.35 (2H, t, J=6.6 Hz), 2.96 (2H, t,J=6.6 Hz), 2.78 (2H, q, J=7.7 Hz), 2.66 (3H, s), 2.50 (3H, s), 2.43 (3H,s), 1.24 (3H, t, J=7.7 Hz).

Example 42-Ethyl-5,7-dimethyl-3-(4-{2-[({methyl[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0626] To a stirred solution of2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(Example 1, 200 mg, 0.41 mmol) in THF (10 mL) was added dropwise asolution of lithium diisopropylamide (LDA) (2.0 N inheptane/hexane/ethylbenzene, 0.8 mL, 1.6 mmol) with ice-cooling over aperiod of 10 min. After completion of the addition, the stirring wascontinued for an additional 20 min at the same temperature. To theresulting mixture was added dropwise Mel (0.5 mL) at 0° C., and stirredat room temperature for 15 h. The mixture was poured into a solution ofphosphate buffer (100 mL) and extracted with dichloromethane (100 mL).The organic layer was washed with brine (50 mL), dried (Na₂SO₄), andconcentrated. The residue was purified by flash chromatography on silicagel eluting with dichloromethane/methanol (10:1) to give 10 mg (5%) ofthe title compound as a colorless oil: ¹H-NMR (CDCl₃) δ 7.64 (2H, d,J=8.3 Hz), 7.53-7.25 (7H, m), 6.89 (1H, s), 3.65-3.55 (2H, m), 3.14 (3H,s), 2.96 (2H, t, J=6.7 Hz), 2.82 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.50(3H, s), 2.40 (3H, s), 1.25 (3H, t, J=7.6 Hz).

Example 52-Ethyl-5,7-dimethyl-3-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0627] Step 1.N-{2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}-N-methylamine

[0628] A mixture of3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 7 of Example 1, 627 mg, 9.0 mmol), a solution of methylamine (40%in methanol, 6 mL) and water (6 mL) was placed in a sealed tube andheated overnight at 130° C. The reaction mixture was partitioned betweendichloromethane (50 mL) and water (50 mL). The organic phase wasseparated and the aqueous phase was extracted with dichloromethane (50mL). The combined organic extracts were washed with brine (50 mL) anddried (Na₂SO₄). After removal of solvent, the crude product was purifiedby flash column chromatography on silica gel eluting withdichloromethane/methanol (5:1) to afford 523 mg (85%) of the titlecompound as white solids: ¹H-NMR (CDCl₃) δ 7.41 (2H, d, J=8.3 Hz), 7.31(2H, d, J=8.3 Hz), 6.90 (1H, s), 4.73 (1H, br. s), 2.93 (4H, s), 2.82(2H, q, J=7.5 Hz), 2.65 (3H, s), 2.51 (3H, s), 2.49 (3H, s), 1.28 (3H,t, J=7.5 Hz).

[0629] Step 2.2-Ethyl-5,7-dimethyl-3-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4.5-b]pyridine

[0630] To a solution ofN-{2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}-N-methylamine(step 1, 523 mg, 1.7 mmol) in dichloromethane (10 mL) and triethylamine(2 mL) was added p-toluenesulfonyl isocyanate (400 mg, 2.0 mmol). Theresulting reaction mixture was stirred at room temperature for 6 h.After removal of solvent, the residue was purified by flash columnchromatography on silica gel eluting with dichloromethane/methanol(10:1) to afford 358 mg (42%) of the title compound as white solids:¹H-NMR (CDCl₃) δ 7.93 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.4 Hz), 7.24(2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.4 Hz), 6.92 (1H, s), 3.66-3.49 (2H,m), 3.51 (3H, s), 2.93-2.70 (4H, m), 2.65 (3H, s), 2.50 (3H, s), 2.38(3H, s), 1.24 (3H, t, J=7.2 Hz).

Example 62-Ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]propyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0631] Step 1. 1-(4-Aminophenyl)-2-propanol

[0632] A mixture of 1-(4-nitrophenyl)-2-propanol (Schadt, F. L.; et al.J.Am.Chem.Soc., 1978, 100, 228., 2.2 g, 12.3 mmol), iron powder (3.3 g,59.1 mmol), ammonium chloride (370 mg, 6.9 mmol), ethanol (48 mL) andwater (24 mL) was heated at reflux temperature for 2 h. The mixture wascooled and filtered through a pad of Celite. The filtrate wasconcentrated. The residue was diluted with ethyl acetate (200 mL) andwashed with water (2×100 mL). The organic layer was dried (MgSO₄), andconcentrated. Purification by flash column chromatography on silica geleluting with hexane/ethyl acetate (1:1) to afford 1.45 g (78%) of thetitle compound as a yellow oil:

[0633]¹H-NMR (CDCl₃) δ 7.00 (2H, d, J=8.6 Hz), 6.64 (2H, d, J=8.8 Hz),3.99-3.89 (1H, m), 3.60 (2H, br s), 2.72-2.52 (2H, m), 1.22 (3H, d,J=6.2 Hz).

[0634] Step 2.1-{4-[(4,6-Dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-propanol

[0635] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 1-(4-aminophenyl)-2-propanol(step 1) and 2-chloro-4,6-dimethyl-3-nitropyridine (step 2 of Example1).

[0636]¹H-NMR (CDCl₃) δ 9.59 (1H, br. s), 7.58 (2H, d, J=8.4 Hz), 7.20(2H, d, J=8.4 Hz), 6.53 (1H, s), 4.13-4.01 (1H, m), 2.82-2.64 (2H, m),2.55 (3H, s), 2.44 (3H, s), 1.25 (3H, d, J=6.2 Hz).

[0637] Step 3.1-{4-[(3-Amino-4,6-dimethyl-2-pryidinyl)amino]phenyl}-2-propanol

[0638] A mixture of1-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-propanol (step2, 500 mg, 1.66 mmol), iron powder (440 mg, 7.88 mmol), ammoniumchloride (80 mg, 1.5 mmol) in ethanol/water (v/v, 31:8, 39 mL) washeated at reflux temperature for 2 h. The mixture was cooled andfiltered through a pad of Celite. The filtrate was concentrated. Theresidue was diluted with dichloromethane (200 mL) and washed with water(2×100 mL). The organic layer was dried (MgSO₄), and concentrated.Removal of solvent gave 450 mg (quant.) of the title compound as brownsolids: TLC Rf 0.10 (hexane/ethyl acetate=1:1).

[0639] Step 4.2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethylpropionate

[0640] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}-2-propanol (step3) and propionyl chloride.

[0641] TLC Rf=0.30 (hexane/ethyl acetate=1:1).

[0642] Step 5.1-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyll-2-propanol

[0643] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethylpropionate (step 4).

[0644]¹H-NMR (CDCl₃) δ 7.40 (2H, d, J=8.0 Hz), 7.33 (2H, d, J=8.0 Hz),6.91 (1H, s), 4.16-4.07 (1H, m), 2.90-2.76 (4H, m), 2.66 (2H, s), 2.52(3H, s), 1.32-1.22 (6H, m).

[0645] Step 6.3-[4-(2-Chloropropyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0646] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from1-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-2-propanol(step 5).

[0647] TLC Rf=0.50 (hexane/ethyl acetate=1:1).

[0648] Step 7.2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethylazide

[0649] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from3-[4-(2-chloropropyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 6).

[0650]¹H-NMR (CDCl₃) δ 7.40 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz),6.91 (1H, s), 3.81-3.74 (1H, m), 2.95-2.79 (4H, m), 2.66 (3H, s), 2.52(3H, s), 1.35 (3H, d, J=6.6 Hz), 1.27 (3H, t, J=7.5 Hz).

[0651] Step 8.1-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-2-propanamine

[0652] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethylazide (step 7).

[0653]¹H-NMR (CDCl₃) δ 7.40-7.31 (4H, m), 6.90 (1H, s), 3.31-3.20 (1H,m), 2.87-2.77 (3H, m), 2.66-2.58 (4H, m), 2.52 (3H, s), 1.28 (3H, t,J=8.3 Hz), 1.19 (3H, d, J=6.8 Hz).

[0654] Step 9.2-Ethyl-5,7-dimethyl-3-(4-{2-1({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]propyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0655] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-2-propanamine(step 8).

[0656] mp 128° C.; MS (ESI) m/z 506.19 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.74(2H, d, J=8.3 Hz), 7.30-7.19 (6H, m), 6.90 (1H, s), 4.08-4.02 (1H, m),2.84-2.72 (4H, m), 2.65 (3H, s), 2.48 (3H, s), 2.32 (3H, s), 1.20-1.13(6H, m).

Example 72-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[0657] The title compound was prepared according to the proceduredescribed in Example 3 from1-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-2-propanol(step 5 of Example 6).

[0658] mp 108° C.; MS (ESI) m/z 507.18 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.91(2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.3 Hz), 7.23 (4H, s), 6.91 (1H, s),5.10-5.04 (1H, m), 2.95-2.76 (4H, m), 2.65 (3H, s), 2.50 (3H, s), 2.41(3H, s), 1.28-1.21 (6H, m).

Example 85,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-propyl-3H-imidazo[4,5-b]pyridine

[0659] Step 1.2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylbutyrate

[0660] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 ofExample 1) and butyryl chloride.

[0661]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz),6.92 (1H, s), 4.39 (2H, t, J=6.4 Hz), 3.09 (2H, t, J=6.4 Hz), 2.77, (2H,t, J=7.7 Hz), 2.66 (3H, s), 2.52 (3H, s), 2.32 (2H, t, J=7.7 Hz),1.81-1.58 (4H, m), 1.00-0.86 (6H, m).

[0662] Step 2.2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0663] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylbutyrate (step 1).

[0664]¹H-NMR (CDCl₃) δ 7.43 (2H, d, J=8.0 Hz), 7.32 (2H, d, J=8.0 Hz),6.90 (1H, s), 4.00-3.89 (2H, m), 2.97 (2H, t, J=6.4 Hz), 2.78 (2H, t,J=7.8 Hz), 2.65 (3H, s), 2.51 (3H, s), 1.80-1.64 (2H, m), 0.92 (3H, t,J=7.4 Hz).

[0665] Step 3.3-[4-(2-Chloroethyl)phenyl]-5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine

[0666] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 2).

[0667] MS (EI) m/z 327 (M⁺).

[0668] Step 4.2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide

[0669] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine(step 3).

[0670] MS (EI) m/z 334 (M⁺); ¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.4 Hz),7.34 (2H, d, J=8.4 Hz), 6.91 (1H, s), 3.60 (2H, t, J=7.2 Hz), 3.00 (2H,t, J=7.2 Hz), 2.77 (2H, t, J=7.8 Hz), 2.65 (3H, s), 2.52 (3H, s),1.75-1.62 (2H, m), 0.90 (3H, t, J=7.4 Hz).

[0671] Step 5.2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0672] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide (step 4).

[0673]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz),6.88 (1H, s), 3.89 (2H, br.s), 3.18 (2H, t, J=6.8 Hz), 3.01 (2H, t,J=6.8 Hz), 2.75 (2H, t, J=7.5 Hz), 2.64 (3H, s), 2.48 (3H, s), 1.78-1.63(2H, m), 0.90 (3H, t, J=7.3 Hz).

[0674] Step 6.5,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-propyl-3H-imidazo[4,5-b]pyridine

[0675] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 5).

[0676]¹H-NMR (CDCl₃) δ 7.86 (2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz),7.23 (2H, d, J=8.3 Hz), 7.16 (2H, d, J=8.3 Hz), 6.90 (1H, s), 6.10 (1H,br.s), 3.58-3.46 (2H, m), 2.87 (2H, t, J=6.4 Hz), 2.71-2.59 (5H, m),2.42 (3H, s), 2.40 (3H, s), 1.74-1.61 (2H, m), 0.89 (3H, t, J=7.0 Hz).

Example 92-Isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0677] Step 1. 5-Bromo-4,6-dimethyl-3-nitro-2-pyridinol

[0678] To a solution of 5-bromo-4,6-dimethyl-3-nitro-2-pyridinylamine(Heitsch, H.; et al. Bioorg. Med. Chem. 1997, 5, 673., 2.0 g, 8.1 mmol)in trifluoroacetic acid/water (v/v, 2:1, 30 mL) was added sodium nitrite(1.1 g, 16 mmol) in small portions at room temperature, and then thereaction mixture was stirred overnight. The resulting precipitates werecollected by filtration, washed with water, and dried under reducedpressure to give 2.2 g (quant.) of the title compound: ¹H-NMR (CDCl₃) δ2.53 (3H, s), 2.38 (3H, s).

[0679] Step 2. 3-Bromo-6-chloro-2,4-dimethyl-5-nitropyridine

[0680] The title compound was prepared according to the proceduredescribed in step 2 of Example 1 from5-bromo-4,6-dimethyl-3-nitro-2-pyridinol (step 1).

[0681]¹H-NMR (CDCl₃) δ 2.72 (3H, s), 2.41 (3H, s).

[0682] Step 3.2-{4-[(5-Bromo-4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

[0683] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from3-bromo-6-chloro-2,4-dimethyl-5-nitropyridine (step 2) and4-aminophenylethyl alcohol.

[0684]¹H-NMR (CDCl₃) δ 8.66 (1H, br.s), 7.51 (2H, d, J=8.4 Hz), 7.22(2H, d, J=8.4 Hz), 3.90-3.77 (2H, m), 2.88 (2H, t, J=6.5 Hz), 2.65 (3H,s), 2.59 (3H, s).

[0685] Step 4.2-{4-[(3-Amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol

[0686] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from2-{4-[(5-bromo-4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol(step 3).

[0687]¹H-NMR (CDCl₃) δ 7.12 (4H, s), 6.21 (1H, s), 3.38 (1H, br.s), 3.82(2H, t, J=6.5 Hz), 2.80 (2H, t, J=6.5 Hz), 2.54 (3H, s), 2.38 (3H, s).

[0688] Step 5.2-[4-(6-Bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl2-methylpropanoate

[0689] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol(step 4) and isobutyryl chloride.

[0690] MS (EI) m/z 457 (M⁺).

[0691] Step 6.2-[4-(6-Bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0692] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(6-bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl2-methylpropanoate (step 5).

[0693]¹H-NMR (CDCl₃) δ 7.45 (2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz),3.96 (2H, t, J=7.3 Hz), 3.15-3.03 (1H, m), 2.97 (2H, t, J=7.3 Hz), 2.76(3H, s), 2.67 (3H, s), 1.34 (6H, d, J=6.8 Hz).

[0694] Step 7.6-Bromo-3-[4-(2-chloroethyl)phenyl]-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0695] The title compound was prepared according to the proceduredescribed in step 7 Example 1 from2-[4-(6-bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 6).

[0696]¹H-NMR (CDCl₃) δ 7.43 (2H, d, J=8.3 Hz), 7.32 (2H, d, J=8.3 Hz),3.81 (2H, t, J=7.3 Hz), 3.19 (2H, t, J=7.3 Hz), 3.15-3.02 (1H, m), 2.76(3H, s), 2.66 (3H, s), 1.33 (6H, d, J=6.9 Hz).

[0697] Step 8.2-[4-(6-Bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide

[0698] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from6-bromo-3-[4-(2-chloroethyl)phenyl]-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 7).

[0699] MS (EI) m/z 412 (M⁺); ¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.4 Hz),7.30 (2H, d, J=8.4 Hz), 3.60 (2H, t, J=6.5 Hz), 3.16-3.02 (1H, m), 3.02(2H, t, J=6.5 Hz), 2.77 (3H, s), 2.68 (3H, s), 1.33 (6H, d, J=6.9 Hz).

[0700] Step 9.[4-(2-Isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0701] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(6-bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide (step 8).

[0702] NMR (CDCl₃) δ 7.49 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz),6.93 (1H, s), 6.60 (2H, br.s), 3.32-3.00 (5H, m), 2.65 (3H, s), 2.48(3H, s), 1.31 (6H, d, J=6.8 Hz).

[0703] Step 10.2-Isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0704] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from[4-(2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 9).

[0705]¹H-NMR (CDCl₃) δ 7.87 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz),7.23 (2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.4 Hz), 6.91 (1H, s), 6.08 (1H,br.s), 3.56-3.43 (2H, m), 3.02-2.89 (1H, m), 2.85 (2H, t, J=6.3 Hz),2.67 (3H, s), 2.41 (6H, s), 1.26 (6H, d, J=6.8 Hz).

Example 102-Isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,sodium salt

[0706] The title compound was prepared according to the proceduredescribed in Example 2 from2-isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(Example 9).

[0707] MS (ESI) m/z 506 (M+H)⁺.

Example 112-Butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0708] Step 1.2-[4-(6-Bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpentanoate

[0709] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol(step 4 of Example 9) and pentanoyl chloride.

[0710] MS (EI) m/z 485 (M⁺); ¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.3 Hz),7.31 (2H, d, J=8.3 Hz), 4.37 (2H, t, J=6.9 Hz), 3.05 (2H, t, J=6.9 Hz),2.79 (2H, t, J=7.7 Hz), 2.75 (3H, s), 2.67 (3H, s), 2.33 (2H, t, J=7.5Hz), 1.75-1.54 (4H, m), 1.40-1.20 (4H, m), 0.91 (3H, t, J=7.3 Hz), 0.84(3H, t, J=7.3 Hz).

[0711] Step 2.2-[4-(6-Bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0712] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(6-bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpentanoate (step 1).

[0713] MS (EI) m/z 401 (M⁺).

[0714] Step 3.6-Bromo-2-butyl-3-[4-(2-chloroethyl)thenyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0715] The title compound was prepared according to the proceduredescribed in step 7 Example 1 from2-[4-(6-bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 2).

[0716] MS (EI) m/z 419 (M⁺).

[0717] Step 4.2-[4-(6-Bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide

[0718] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from6-bromo-2-butyl-3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 3).

[0719] MS (EI) m/z 426 (M⁺); ¹H-NMR (CDCl₃) δ 7.43 (2H, d, J=8.4 Hz),7.33 (2H, d, J=8.4 Hz), 3.61 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz),2.79 (2H, t, J=7.9 Hz), 2.75 (3H, s), 2.67 (3H, s), 1.75-1.60 (2H, m),1.36-1.20 (2H, m), 0.84 (3H, t, J=7.3 Hz).

[0720] Step 5.2-[4-(2-Butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0721] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(6-bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide (step 4).

[0722]¹H-NMR (CDCl₃) δ 7.59 (2H, d, J=8.3 Hz), 7.35 (2H, d, J=8.3 Hz),6.90 (1H, s), 3.52-3.22 (4H, m), 3.01 (2H, br.s), 2.90 (2H, t, J=7.7Hz), 2.74 (3H, s), 2.56 (3H, s), 1.79-1.62 (2H, m), 1.41-1.23 (2H, m),0.84 (3H, t, J=7.5 Hz).

[0723] Step 6.2-Butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0724] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 5).

[0725]¹H-NMR (CDCl₃) δ 7.86 (2H, d, J=8.2 Hz), 7.31 (2H, d, J=8.2 Hz),7.22 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.3 Hz), 6.91 (1H, s), 6.09 (1H,br.s), 3.56-3.44 (2H, m), 2.84 (2H, t, J=6.4 Hz), 2.70-2.59 (5H, m),2.42 (3H, s), 2.41 (3H, s), 1.69-1.43 (2H, m), 1.30-1.18 (2H, m), 0.80(3H, t, J=7.3 Hz).

Example 122-Butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,sodium salt

[0726] The title compound was prepared according to the proceduredescribed in Example 2 from2-butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(Example 11).

[0727] MS (ESI) m/z 520 (M+H)⁺.

Example 132-Isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0728] Step 1.2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl3-methylbutanoate

[0729] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 ofExample 1) and isovaleryl chloride.

[0730] MS (EI) m/z 407 (M⁺).

[0731] Step 2.2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0732] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl3-methylbutanoate (step 1).

[0733] MS (EI) m/z 323 (M⁺).

[0734] Step 3.3-[4-(2-Chloroethyl)phenyl]-2-isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0735] The title compound was prepared according to the proceduredescribed in step 7 Example 1 from2-[4-(2-isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 2).

[0736] MS (EI) m/z 341 (M⁺); ¹H-NMR (CDCl₃) δ 7.41 (2H, d, J=8.2 Hz),7.33 (2H, d, J=8.2 Hz), 6.90 (1H, s), 3.80 (2H, t, J=6.5 Hz), 3.18 (2H,t, J=6.5 Hz), 2.68 (2H, d, J=7.5 Hz), 2.66 (3H, s), 2.51 (3H, s),2.14-1.96 (1H, m), 0.86 (6H, d, J=6.6 Hz).

[0737] Step 4.2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide

[0738] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from3-[4-(2-chloroethyl)phenyl]-2-isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 3).

[0739] MS (EI) m/z 348 (M⁺); ¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.4 Hz),7.31 (2H, d, J=8.4 Hz), 6.91 (1H, s), 3.60 (2H, t, J=6.5 Hz), 3.00 (2H,t, J=6.5 Hz), 2.69 (2H, d, J=7.5 Hz), 2.65 (3H, s), 2.52 (3H, s),2.08-1.98 (1H, m), 0.87 (6H, d, J=6.7 Hz).

[0740] Step 5.2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0741] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide (step 4).

[0742]¹H-NMR (CDCl₃) δ 7.40 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz),6.91 (1H, s), 3.09 (2H, t, J=6.4 Hz), 2.93 (2H, t, J=6.4 Hz), 2.80 (2H,br.s), 2.68 (2H, d, J=7.5 Hz), 2.66 (3H, s), 2.53 (3H, s), 2.18-2.00(1H, m), 0.88 (6H, d, J=6.8 Hz).

[0743] Step 6.2-Isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0744] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 5).

[0745]¹H-NMR (CDCl₃) δ 7.85 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz),7.21 (2H, d, J=8.3 Hz), 7.12 (2H, d, J=8.3 Hz), 6.91 (1H, s), 6.14 (1H,br.s), 3.55-3.42 (2H, m), 2.82 (2H, t, J=6.3 Hz), 2.65 (3H, s), 2.53(2H, d, J=7.3 Hz), 2.41 (3H, s), 2.39 (3H, s), 2.10-1.92 (1H, m), 0.81(6H, d, J=6.6 Hz).

Example 142-Isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,sodium salt

[0746] The title compound was prepared according to the proceduredescribed in Example 2 from2-isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(Example 13).

[0747] MS (ESI) m/z 520 (M+H)⁺.

Example 155,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-neopentyl-3H-imidazo[4,5-b]pyridine

[0748] Step 1.2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl3,3-dimethylbutanoate

[0749] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 ofExample 1) and tert-butylacetyl chloride.

[0750] MS (EI) m/z 435 (M⁺).

[0751] Step 2.2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0752] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl3,3-dimethylbutanoate (step 1).

[0753] MS (EI) m/z 337 (M⁺).

[0754] Step 3.3-[4-(2-Chloroethyl)phenyl]-2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0755] The title compound was prepared according to the proceduredescribed in step 7 Example 1 from2-[4-(2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 2).

[0756]¹H-NMR (CDCl₃) δ 7.41 (2H, d, J=8.2 Hz), 7.30 (2H, d, J=8.2 Hz),6.89 (1H, s), 3.81 (2H, t, J=6.5 Hz), 3.18 (2H, t, J=6.5 Hz), 2.79 (2H,s), 2.66 (3H, s), 2.51 (3H, s), 0.89 (9H, s).

[0757] Step 4.2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide

[0758] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from3-[4-(2-chloroethyl)phenyl]-2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 3).

[0759] MS (EI) m/z 362 (M⁺); ¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.3 Hz),7.31 (2H, d, J=8.3 Hz), 6.91 (1H, s), 3.62 (2H, t, J=6.5 Hz), 3.02 (2H,t, J=6.5 Hz), 2.78 (2H, s), 2.68 (3H, s), 2.53 (3H, s), 0.88 (9H, s).

[0760] Step 5.2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0761] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide (step 4).

[0762] MS (EI) m/z 336 (M⁺).

[0763] Step 6.2-Neopentyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0764] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 5).

[0765]¹H-NMR (CDCl₃) δ 7.86 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz),7.22 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.3 Hz), 6.91 (1H, s), 6.18 (1H,br.s), 3.56-3.46 (2H, m), 2.85 (2H, t, J=6.4 Hz), 2.65 (3H, s), 2.60(2H, s), 2.41 (3H, s), 2.40 (3H, s), 0.87 (9H, s).

Example 165,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-neopentyl-3H-imidazo[4,5-b]pyridine,sodium salt

[0766] The title compound was prepared according to the proceduredescribed in Example 2 from5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-neopentyl-3H-imidazo[4,5-b]pyridine(Example 15).

[0767] MS (ESI) m/z 534 (M+H)⁺.

Example 175,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine

[0768] Step 1.N-[4-(2-Chloroethyl)phenyl]-N-(4,6-dimethyl-3-nitro-2-pyridinyl)amine

[0769] The title compound was prepared according to the proceduredescribed in step 7 Example 1 from2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 3 ofExample 1).

[0770]¹H-NMR (CDCl₃) δ 9.46 (1H, br.s), 8.29 (1H, d, J=8.8 Hz), 7.42(1H, d, J=1.7 Hz), 7.35 (2H, d, J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz), 6.97(1H, dd, J=8.8, 1.7 Hz), 3.77 (2H, t, J=7.2 Hz), 3.13 (2H, t, J=7.2 Hz).

[0771] Step 2.N²-[4-(2-Chloroethyl)phenyl]-4,6-dimethyl-2,3-pyridinediamine

[0772] The title compound was prepared according to the proceduredescribed in step 3 of Example 6 fromN-[4-(2-chloroethyl)phenyl]-N-(4,6-dimethyl-3-nitro-2-pyridinyl)amine(step 1).

[0773] MS (EI) m/z 383 (M⁺).

[0774] Step 3.3-[4-(2-Chloroethyl)phenyl]-5,7-dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine

[0775] To a mixture ofN²-[4-(2-chloroethyl)phenyl]-4,6-dimethyl-2,3-pyridinediamine (step 2,276 mg, 1.0 mmol) and 3-(1,3-thiazol-2-yl)propanoic acid (157 mg, 1.0mmol) in dichloromethane (10 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (WSC) (192mg, 1.0 mmol) in one portion. The reaction mixture was stirred overnightat room temperature. The reaction mixture was concentrated under reducedpressure. The residue was suspended in toluene (20 mL) and heated at150° C. for 5 h. The reaction mixture was poured into water (50 mL), theorganic phase was separated, and the aqueous phase was extracted withethyl acetate (100 mL). The combined organic phases were washed withbrine (50 mL) and dried (Na₂SO₄). After removal of solvent, the crudeproduct was purified by flash column chromatography on silica geleluting with hexane/ethyl acetate (1:1) to afford 210 mg (53%) of thetitle compound: MS (EI) m/z 396 (M⁺); ¹H-NMR (CDCl₃) δ 7.63 (1H, d,J=3.4 Hz), 7.39 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.15 (1H, d,J=3.4 Hz), 6.93 (1H, s), 3.78 (2H, t, J=7.4 Hz), 3.69-3.50 (2H, m),3.39-3.20 (2H, m), 3.15 (2H, t, J=7.4 Hz), 2.66 (3H, s), 2.53 (3H, s).

[0776] Step 4.2-(4-{5,7-Dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethylazide

[0777] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine(step 3).

[0778] MS (EI) m/z 403 (M⁺); ¹H-NMR (CDCl₃) δ 7.63 (1H, d, J=3.5 Hz),7.38 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.15 (1H, d, J=3.5 Hz),6.93 (1H, s), 3.63-3.54 (4H, m), 3.34-3.26 (2H, m), 2.98 (2H, t, J=7.4Hz), 2.68 (3H, s), 2.53 (3H, s).

[0779] Step 5.2-(4-{5,7-Dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethylamine

[0780] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-(4-{5,7-dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethylazide (step 4).

[0781] MS (EI) m/z 377 (M⁺).

[0782] Step 6.5,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazole-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine

[0783] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-(4-{5,7-dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethylamine(step 5).

[0784] MS (ESI) m/z 575 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.83 (2H, d, J=8.3 Hz),7.61 (1H, d, J=3.5 Hz), 7.32 (2H, d, J=8.3 Hz), 7.19-7.15 (3H, m), 7.07(2H, d, J=8.2 Hz), 6.91 (1H, s), 6.21 (1H, br.s), 3.52-3.40 (4H, m),3.20-3.13 (2H, m), 2.81 (2H, t, J=6.1 Hz), 2.65 (3H, s), 2.44 (3H, s),2.41 (3H, s).

Example 183-{4-[2-({[(4-Biphenylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0785] Step 1. Phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate

[0786] To a stirred solution of2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 9 of Example 1, 1.55 g, 5.3 mmol) and triethylamine (0.80 mL, 5.8mmol) in dichloromethane (26 mL) cooled in an ice bath was addeddropwise phenyl chloroformate (0.69 mL, 5.5 mmol), and the mixture wasstirred at ambient temperature. After 30 min, the reaction mixture waspartitioned between saturated aqueous sodium bicarbonate (30 mL) anddichloromethane (30 mL). The organic layer was separated and the aqueousphase was extracted with dichloromethane (30 mL). The combined organicphases were dried (Na₂SO₄) and concentrated under reduced pressure. Theresidue was recrystallized from dichloromethane/hexane to give 1.90 g(87%) of the title compound as pale brown crystals: ¹H-NMR (CDCl₃) δ7.43-7.11 (9H, m), 6.91 (1H, s), 5.50 (1H, br.s), 3.57 (2H, pseudo q,J=6.9 Hz), 2.98 (2H, t, J=6.9 Hz), 2.83 (2H, q, J=7.6 Hz), 2.66 (3H, s),2.52 (3H, s), 1.28 (3H, t, J=7.6 Hz).

[0787] Step 2.3-{4-[2-({[(4-Biphenylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0788] To a stirred solution of 4-biphenylsulfonamide (Greenlee, W. J.;Walsh, T. F.; et al. Eur. Pat. Appl., EP 617001 (1994)., 56 mg, 0.24mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 20 mg, 0.5 mmol)at room temperature. After 5 min, phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1, 100 mg, 0.24 mmol) was added, and the mixture was stirred foran additional 1 h. The mixture was poured into water (50 mL) andextracted with diethyl ether (2×50 mL). The combined extracts werewashed with water (50 mL), brine (50 mL) and dried (MgSO₄). Removal ofsolvent gave white oily solids. Purification by preparative TLC (ethylacetate) gave 66 mg (50%) of the title compound as a colorless oil: MS(ESI) m/z 554 (M+H)⁺; ¹H-NMR (CDCl₃) δ 8.06 (2H, d, J=8.6 Hz), 7.13 (2H,d, J=8.6 Hz), 7.60-7.53 (2H, m), 7.48-7.36 (3H, m), 7.21 (2H, d, J=8.4Hz), 7.12 (2H, d, J=8.3 Hz), 6.92 (1H, s), 6.11 (1H, br.t, J=5.5 Hz),3.54 (2H, dt, J=5.9, 6.0 Hz), 2.89 (2H, d, J=6.0 Hz), 2.64 (2H, q, J=7.5Hz), 2.66 (3H, s), 2.40 (3H, s), 1.18 (3H, t, J=7.5 Hz).

Example 192-Ethyl-5,7-dimethyl-3-{4-[2-({[(1-naphthylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-3H-imidazo[4,5-b]pyridine

[0789] The title compound was prepared according to the proceduredescribed in step 2 of Example 18 from phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 18) and 1-naphtylsulfonamide (Arnswald, M.; Neumann,W. P. Chem. Ber., 1991, 124, 1997; Khorgami, M. H. Synthesis, 1972,574).

[0790] MS (ESI) m/z 528 (M+H)⁺; ¹H-NMR (CDCl₃) δ 8.52-8.48 (1H, m), 8.36(1H, dd, J=1.1, 7.3 Hz), 8.11 (1H, d, 8.3 Hz), 8.00-7.94 (1H, m),7.63-7.50 (3H, m), 7.20 (2H, d, J=8.4 Hz), 7.13 (2H, d, J=8.4 Hz), 6.94(1H, s), 6.32 (1H, br.t, J=5.7 Hz), 3.50 (2H, dt, J=5.9, 6.0 Hz), 2.82(2H, t, J=6.2 Hz), 2.68 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.41 (3H, s),1.21 (3H, t, J=7.5 Hz).

Example 202-Ethyl-5,7-dimethyl-3-{4-[2-({[(2-naphthylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-3H-imidazo[4,5-b]pyridine

[0791] The title compound was prepared according to the proceduredescribed in step 2 of Example 18 from phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 18) and 2-naphtylsulfonamide.

[0792] MS (ESI) m/z 528 (M+H)⁺; ¹H-NMR (CDCl₃) δ 8.60 (1H, s), 8.01-7.84(5H, m), 7.64-7.52 (2H, m), 7.20-7.08 (4H, m), 6.92 (1H, s), 6.20 (1H,t, J=5.6 Hz), 3.52-3.45 (2H, q, J=6.1 Hz), 2.84-2.80 (2H, t, J=6.3 Hz),2.71-2.62 (2H, q, J=6.6 Hz), 2.66 (3H, s), 2.43 (3H, s), 1.22-1.16 (3H,t, J=6.6 Hz).

Example 212-Ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0793] The title compound was prepared according to the proceduredescribed in step 2 of Example 18 from phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 18) and 2-thiophenesulfonamide (Huang, H. C.;Reinhard, E. J.; Reitz, D. B. Tetrahedron Lett., 1994, 35, 7201.;Graham, S. L.; Scholz, T. H. Synthesis, 1986, 1031).

[0794]¹H-NMR (CDCl₃) δ 8.01 (1H, s), 7.78 (1H, dd, J=1.3, 4.9 Hz), 7.63(1H, dd, J=1.3, 4.9 Hz), 7.22 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.3 Hz),7.09 (1H, dd, J=3.8, 5.0 Hz), 6.92 (1H, s), 6.05 (1H, t, J=5.3 Hz), 3.53(2H, q, J=6.2 Hz), 2.96 (3H, s), 2.88 (3H, s), 2.87 (2H, t, J=6.2 Hz),2.67 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.43 (3H, s), 1.20 (3H, t, J=7.5Hz).

Example 223-(4-{2-[({[(5-Chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0795] The title compound was prepared according to the proceduredescribed in step 2 of Example 18 from phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 18) and 5-chloro-2-thiophenesulfonamide.

[0796] MS (ESI) m/z 518 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.99 (1H, s), 7.58-7.56(1H, m), 7.23-7.15 (4H, m), 6.94-6.92 (1H, m), 6.04 (1H, br), 3.53-3.51(2H, m), 2.87 (2H, m), 2.73-2.65 (2H, q, J=7.6 Hz), 2.65 (3H, s), 2.44(3H, s), 1.21 (3H, t, J=7.6 Hz).

Example 233-(4-{2-[({[(4,5-Dichloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0797] The title compound was prepared according to the proceduredescribed in step 2 of Example 18 from phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 18) and 5,6-dichloro-2-thiophenesulfonamide.

[0798] MS (ESI) m/z 552 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.49 (1H, s), 7.27-7.14(4H, m), 6.84 (1H, s), 3.47 (2H, br), 2.75 (2H, br), 2.69 (2H, q, J=7.6Hz), 2.64 (3H, s), 2.38 (3H, s), 1.22 (3H, t, J=7.6 Hz).

Example 243-{4-[2-({[(1-Benzothien-2-ylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0799] The title compound was prepared according to the proceduredescribed in step 2 of Example 18 from phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 18) and 1-benzothiophene-2-sulfonamide (Chern, J.;Leu, Y.; et al. J. Med. Chem., 1997, 40, 2276.; Graham, S. L.; Shepard,K. L.; et al. J. Med. Chem., 1989, 32, 2548).

[0800] mp 128.0-130.0° C.; MS (ESI) m/z 534 (M+H)⁺; ¹H-NMR (DMSO-d₆) δ8.05-8.00 (3H, m), 7.50-7.42 (2H, m), 7.36 (2H, d, J=7.4 Hz), 7.32 (2H,d, J=7.4 Hz), 6.96 (1H, s), 6.61-6.56 (1H, m), 3.34-3.28 (2H, m), 2.80(2H, t, J=6.6 Hz), 2.68 (2H, q, J=7.5 Hz), 2.54 (3H, s), 2.40 (3H, s),1.19 (3H, t, J=7.5 Hz).

Example 253-(4-{2-[({[(2-Chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[0801] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 9 of Example 1) and 2-chlorobenzenesulfonyl isocyanate.

[0802] MS (ESI) m/z 512 (M+H)⁺; ¹H-NMR (CDCl₃) δ 8.21-8.17 (1H, d, 7.7Hz), 7.57-7.43 (3H, m), 7.32-7.22 (4H, m), 6.93 (s, 1H), 6.34 (1H, t,J=5.6 Hz), 3.56-3.49 (2H, q, J=6.3 Hz), 2.89-2.85 (2H, t, J=6.4 Hz),2.80-2.71 (q, 2H, J=7.6 Hz), 2.67 (3H, s), 2.49 (3H, s), 1.28-1.22 (3H,t, J=7.6 Hz).

Example 262-Ethyl-5-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0803] Step 1. 2-{4-[(6-Methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

[0804] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2-chloro-6-methyl-3-nitropyridine(Takayama, K.; Iwata, M.; Kono, N.; et al. Jpn. Kokai Tokkyo Koho,JP11292877 (1999).; Ding, C. Z.; Hunt, J. T.; Kim, S.; et al. PCT Int.Appl., WO 9730992 (1997)) and 4-aminophenylethyl alcohol.

[0805]¹H-NMR (CDCl₃) δ 8.24 (1H, d, J=9.1 Hz), 7.28-7.33 (4H, m), 6.65(1H, d, J=9.2 Hz), 3.89 (2H, d, J=6.4 Hz), 2.89 (2H, d, J=6.4 Hz), 2.81(3H, s).

[0806] Step 2. 2-{4-[(3-Amino-6-methyl-2-pyridinyl)amino]phenyl}ethanol

[0807] To a solution of2-{4-[(6-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1, 4.6 g,16.9 mmol) in methanol (100 mL) was added 10% Pd—C (300 mg). Theresulting mixture was stirred for 2 h under hydrogen atmosphere. Themixture was filtered through a pad of Celite and the filtrate wasconcentrated. The residue was purified by flash column chromatographyeluting with hexane/ethyl acetate (gradient elution from 1:2 to 1:5) toafford 3.8 g (92%) of the title compound as yellow solids: ¹H-NMR(CDCl₃) δ: 7.10-7.16 (4H, m), 6.91 (1H, d, J=8.4 Hz), 6.70 (1H, d, J=8.4Hz), 6.19 (1H, s), 3.83 (2H, t, J=6.4 Hz), 2.81 (2H, t, J=6.4 Hz), 2.35(3H, s).

[0808] Step 3.2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[0809] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-6-methyl-2-pyridinyl)amino]phenyl}ethanol (step 2) andpropionyl chloride.

[0810] MS (EI) m/z 337 (M⁺).

[0811] Step 4.2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0812] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 3).

[0813]¹H-NMR (CDCl₃) δ 7.90 (1H, d, J=8.3 Hz), 7.43 (2H, d, J=8.2 Hz),7.34 (2H, d, J=8.2 Hz), 7.07 (1H, d, J=8.3 Hz), 3.93 (2H, t, J=6.6 Hz),2.97 (2H, t, J=6.6 Hz), 2.80 (2H, q, J=7.5 Hz), 2.56 (3H, s), 1.35 (3H,t, J=7.5 Hz).

[0814] Step 5.2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide

[0815] A mixture of2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 4, 217 mg, 0.77 mmol) in THF (20 mL) was added diethylazodicarboxylate (DEAD) (0.3 mL, 1.5 mmol), triphenylphosphine (380 mg,1.5 mmol) and diphenylphosphoryl azide (DPPA) (0.4 mL, 1.5 mmol). Themixture was stirred at room temperature for 4.5 h. After removal ofsolvent, the residue was purified by flash column chromatography onsilica gel eluting with hexane/ethyl acetate (gradient elution from 1:1to 1:2) to afford 70 mg (30%) of the title compound as a brown oil:

[0816]¹H-NMR (CDCl₃) δ 7.90 (1H, d, J=8.1 Hz), 7.34-7.44 (4H, m), 7.08(1H, d, J=8.1 Hz), 3.60 (2H, t, J=7.1 Hz), 3.00 (2H, t, J=7.1 Hz), 2.80(2H, q, J=7.5 Hz), 2.57 (3H, s), 1.35 (3H, t, J=7.5 Hz).

[0817] Step 6.2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0818] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide(step 5).

[0819]¹H-NMR (CDCl₃) δ 7.91 (1H, d, J=8.1 Hz), 7.42 (2H, d, J=8.3 Hz),7.32 (2H, d, J=8.3 Hz), 7.06 (1H, d, J=8.1 Hz), 3.13 (2H, t, J=6.8 Hz),2.95 (2H, t, J=6.8 Hz), 2.81 (2H, q, J=7.6 Hz), 2.55 (3H, s), 1.34 (3H,t, J=7.6 Hz).

[0820] Step 7.2-Ethyl-5-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0821] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 6).

[0822] MS (ESI) m/z 476 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.95 (1H, d, J=8.0 Hz),7.84 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.25 (2H, d, J=8.2 Hz),7.17 (2H, d, J=8.2 Hz), 7.10 (1H, d, J=8.0 Hz), 6.17 (1H, br.s), 3.52(2H, t, J=6.6 Hz), 2.86 (2H, t, J=6.6 Hz), 2.69 (2H, q, J=7.5 Hz), 2.49(3H, s), 2.41 (3H, s), 1.27 (3H, t, J=7.5 Hz).

Example 272-Ethyl-5-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,sodium salt

[0823] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-5-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(Example 26).

[0824]¹H-NMR (DMSO-d₆) δ 7.91 (1H, d, J=7.9 Hz), 7.61 (2H, d, J=6.8 Hz),7.36 (4H, s), 7.11-7.15 (3H, m), 2.67-2.75 (4H, m), 2.50 (2H, br.s),2.45 (3H, s), 2.28 (3H, s), 1.21-1.24 (3H, m).

Example 282-Ethyl-5-methoxy-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0825] Step 1. 2-{4-[(6-Methoxy-3-nitro-2-pyridinyl)amino]phenyl}ethanol

[0826] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2-chloro-6-methoxy-3-nitropyridineand 4-aminophenylethyl alcohol.

[0827]¹H-NMR (CDCl₃) δ 10.59 (1H, br.s), 8.38 (1H, d, J=9.2 Hz), 7.59(2H, d, J=8.3 Hz), 7.23 (2H, d, J=8.3 Hz), 6.20 (1H, d, J=9.2 Hz), 3.94(3H, s), 3.87 (2H, t, J=6.6 Hz), 2.87 (2H, t, J=6.6 Hz).

[0828] Step 2. 2-{4-[(3-Amino-6-methoxy-2-pyridinyl)amino]phenyl}ethanol

[0829] A mixture of2-{4-[(6-methoxy-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1, 3.52g, 12.17 mmol), iron powder (3.4 g, 60.84 mmol) and ammonium chloride(325 mg, 6.08 mmol) in ethanol/water (v/v, 2:1, 90 mL) was heated atreflux temperature for 1 h. After cooling, the catalyst was removed andthe filtrate was concentrated. The residue was extracted with ethylacetate (100 mL) and washed with water. The organic layer was dried(MgSO₄), and concentrated to give 3.41 g (quant.) of the title compoundas a black oil: ¹H-NMR (CDCl₃) δ 7.48 (2H, d, J=8.4 Hz), 7.14 (2H, d,J=8.4 Hz), 7.04 (1H, d, J=8.2 Hz), 6.75 (1H, br.s), 6.13 (1H, d, J=8.2Hz), 3.87 (3H, s), 3.83 (2H, t, J=6.6 Hz), 2.81 (2H, t, J=6.6 Hz).

[0830] Step 3.2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[0831] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-6-methoxy-2-pyridinyl)amino]phenyl}ethanol (step 2) andpropionyl chloride.

[0832] TLC Rf=0.50 (hexane/ethyl acetate=2:1).

[0833] Step 4.2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0834] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 3).

[0835]¹H-NMR (CDCl₃) δ 7.91 (1H, d, J=8.6 Hz), 7.43 (2H, d, J=8.4 Hz),7.35 (2H, d, J=8.4 Hz), 6.67 (1H, d, J=8.6 Hz), 3.98-3.88 (2H, m), 3.82(3H, s), 2.99 (2H, t, J=6.4 Hz), 2.81 (2H, q, J=7.4 Hz), 1.34 (3H, t,J=7.4 Hz).

[0836] Step 5.2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide

[0837] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-(4-(2-ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethanol(step 4).

[0838] TLC Rf=0.78 (hexane/ethyl acetate=1/1).

[0839] Step 6.2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0840] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide(step 5).

[0841]¹H-NMR (CDCl₃) δ 7.92 (1H, d, J=8.6 Hz), 7.40-7.31 (4H, m), 6.67(1H, d, J=8.6 Hz), 3.82 (3H, s), 3.13-3.10 (2H, m), 3.00-2.97 (2H, m),2.80 (2H, q, J=7.6 Hz), 1.33 (3H, t, J=7.6 Hz).

[0842] Step 7.2-Ethyl-5-methoxy-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0843] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 6).

[0844]¹H-NMR (CDCl₃) δ 7.95 (1H, d, J=8.7 Hz), 7.74 (2H, d, J=8.4 Hz),7.34-7.27 (6H, m), 6.69 (1H, d, J=8.7 Hz), 6.55 (1H, m), 3.79 (3H, s),3.60-3.53 (2H, m), 2.90 (2H, t, J=6.8 Hz), 2.77 (2H, q, J=7.4 Hz), 1.30(3H, t, J=7.4 Hz).

Example 292-Ethyl-5-methoxy-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,sodium salt

[0845] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-5-methoxy-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(Example 28).

[0846]¹H-NMR (DMSO-d₆) δ 7.94 (1H, d, J=8.4 Hz), 7.59 (2H, d, J=8.1 Hz),7.41-7.34 (4H, m), 7.12 (2H, d, J=8.1 Hz), 6.68 (1H, d, J=8.4 Hz), 3.71(3H, s), 3.14 (2H, m), 2.75-2.68 (4H, m), 2.27 (3H, s), 1.20 (3H, t,J=7.5 Hz); IR (KBr) ν_(max) 1597, 1518, 1489, 1425, 1389, 1261, 1130,1086 cm⁻¹.

Example 302-Ethyl-6-methyl-3-(4-{2-[({[(methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0847] Step 1. 2-{4-[(5-Methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

[0848] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2-chloro-5-methyl-3-nitropyridineand 4-aminophenylethyl alcohol.

[0849]¹H-NMR (CDCl₃) δ 9.96 (1H, br.s), 8.32-8.31 (2H, m), 7.55 (2H, d,J=8.3 Hz), 7.24 (2H, d, J=8.3 Hz), 3.85 (2H, m), 2.86 (2H, t, J=6.6 Hz),2.32 (3H, s).

[0850] Step 2. 2-{4-[(3-Amino-5-methyl-2-pyridinyl)amino]phenyl}ethanol

[0851] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{4-[(5-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1).

[0852]¹H-NMR (CDCl₃) δ 7.59 (1H, m), 7.08-7.00 (4H, m), 6.80 (1H, m),3.74 (2H, t, J=6.6 Hz), 2.74 (2H, t, J=6.6 Hz), 2.19 (3H, s).

[0853] Step 3.2-[4-(2-Ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[0854] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-5-methyl-2-pyridinyl)amino]phenyl}ethanol (step 2) andpropionyl chloride.

[0855] TLC Rf=0.74 (dichloromethane/methanol=10:1).

[0856] Step 4.2-[4-(2-Ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0857] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 3).

[0858]¹H-NMR (CDCl₃) δ 8.12 (1H, s), 7.84 (1H, s), 7.44 (2H, d, J=8.1Hz), 7.33 (2H, d, J=8.1 Hz), 3.91-3.85 (2H, m), 2.96 (2H, t, J=6.7 Hz),2.82 (2H, q, J=7.5 Hz), 2.46 (3H, s), 1.36 (3H, t, J=7.5 Hz).

[0859] Step 5.2-[4-(2-Ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide

[0860] The title compound was prepared according to the proceduredescribed in step 5 Example 26 from2-[4-(2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 4).

[0861]¹H-NMR (CDCl₃) δ 8.13 (1H, s), 7.84 (1H, s), 7.44 (2H, d, J=8.4Hz), 7.36 (2H, d, J=8.4 Hz), 3.59 (2H, t, J=7.3 Hz), 3.00 (2H, t, J=7.3Hz), 2.83 (2H, q, J=7.6 Hz), 2.46 (3H, s), 1.36 (3H, t, J=7.6 Hz).

[0862] Step 4.2-[4-(2-Ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0863] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide(step 5).

[0864]¹H-NMR (CDCl₃) δ 8.12 (1H, s), 7.84 (1H, s), 7.42 (2H, d, J=8.4Hz), 7.33 (2H, d, J=8.4 Hz), 3.07 (2H, t, J=6.8 Hz), 2.91-2.78 (4H, m),2.46 (3H, s), 1.36 (3H, t, J=7.5 Hz).

[0865] Step 5.2-Ethyl-6-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0866] The reaction was carried out according to the procedure describedin step 10 of Example 1 from2-[4-(2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 6).

[0867]¹H-NMR (CDCl₃) δ 8.04 (1H, d, J=1.8 Hz), 7.86-7.82 (3H, m),7.33-7.21 (6H, m), 6.27 (1H, m), 3.52-3.49 (2H, m), 2.87 (2H, t, J=6.8Hz), 2.76 (2H, q, J=7.6 Hz), 2.45 (3H, s), 2.41 (3H, s), 1.30 (3H, t,J=7.6 Hz).

Example 312-Ethyl-6-methyl-3-(4-{2-[({[(methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,sodium salt

[0868] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-6-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(Example 30).

[0869]¹H-NMR (DMSO-d₆) δ 8.04 (1H, m), 7.84 (1H, m), 7.60 (2H, d, J=8.1Hz), 7.36 (4H, s), 7.12 (2H, d, J=8.1 Hz), 3.13 (2H, m), 2.78-2.71 (4H,m), 2.39 (3H, s), 2.27 (3H, s), 1.22 (3H, t, J=7.5 Hz); IR (KBr) ν_(max)1601, 1518, 1423, 1375, 1283, 1250, 1128, 1084 cm⁻¹.

Example 326-Chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0870] Step 1. 2-{4-[(5-Chloro-3-nitro-2-pyridinyl)amino]phenyl}ethanol

[0871] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,5-dichloro-3-nitropyridine(Marfat, A.; Robinson, R. P. US pat. Appl., U.S. Pat. No. 5,811,432(1998).; Haessig, R.; Siegrist, U. Eur. Pat. Appl., EP 483061 (1992).)and 4-aminophenylethyl alcohol.

[0872]¹H-NMR (CDCl₃) δ 10.00 (1H, br.s), 8.51-8.50 (1H, m), 8.41 (1H, d,J=2.4 Hz), 7.53 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 3.88-3.87(2H, m), 2.88 (2H, t, J=6.6 Hz).

[0873] Step 2. 2-{4-[(3-Amino-5-chloro-2-pyridinyl)amino]phenyl}ethanol

[0874] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{4-[(5-chloro-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1).

[0875]¹H-NMR (CDCl₃) δ 7.73 (1H, d, J=2.2 Hz), 7.19-7.01 (4H, m), 6.97(1H, d, J=2.2 Hz), 6.12 (1H, br.s), 3.81 (2H, t, J=6.4 Hz), 2.80 (2H, t,J=6.4 Hz).

[0876] Step 3.2-[4-(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[0877] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-5-chloro-2-pyridinyl)amino]phenyl}ethanol (step 2).

[0878] TLC Rf=0.43 (hexane/ethyl acetate=2:1).

[0879] Step 4.2-[4-(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0880] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(6-chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 3).

[0881]¹H-NMR (CDCl₃) δ 8.23 (1H, d, J=2.1 Hz), 8.01 (1H, d, J=2.1 Hz),7.45 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.09 (1H, s), 3.92 (2H,t, J=6.4 Hz), 2.95 (2H, t, J=6.4 Hz), 2.83 (2H, q, J=7.4 Hz), 1.36 (3H,t, J=7.4 Hz).

[0882] Step 5.2-[4-(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide

[0883] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-[4-(6-chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 4).

[0884]¹H-NMR (CDCl₃) δ 8.25 (1H, d, J=2.2 Hz), 8.02 (1H, d, J=2.2 Hz),7.46 (2H, d, J=8.3 Hz), 7.35 (2H, d, J=8.3 Hz), 3.60 (2H, t, J=7.2 Hz),3.00 (2H, t, J=7.2 Hz), 2.84 (2H, q, J=7.5 Hz), 1.37 (3H, t, J=7.5 Hz).

[0885] Step 6.2-[4-(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0886] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(6-chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide(step 5).

[0887]¹H-NMR (CDCl₃) δ 8.22 (1H, d, J=2.1 Hz), 8.01 (1H, d, J=2.1 Hz),7.45 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 3.13-3.08 (2H, m),2.95-2.78 (4H, m), 1.36 (3H, t, J=7.6 Hz).

[0888] Step 7.6-Chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0889] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(6-chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 6).

[0890]¹H-NMR (CDCl₃) δ 8.20 (1H, d, J=2.2 Hz), 8.03 (1H, d, J=2.2 Hz),7.77 (2H, d, J=8.1 Hz), 7.38-7.27 (6H, m), 6.51-6.48 (1H, m), 3.57-3.50(2H, m), 2.90 (2H, t, J=6.8 Hz), 2.81 (2H, t, J=7.5 Hz), 1.34 (3H, t,J=7.5 Hz).

Example 336-Chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,sodium salt

[0891] The title compound was prepared according to the proceduredescribed in Example 2 from6-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(Example 32).

[0892]¹H-NMR (DMSO-d₆) δ 8.24-8.21 (2H, m), 7.60 (2H, d, J=8.1 Hz),7.42-7.34 (4H, m), 7.12 (2H, d, J=8.1 Hz), 3.13 (2H, m), 2.81-2.69 (4H,m), 2.27 (3H, s), 1.24 (3H, t, J=7.4 Hz); IR (KBr) ν_(max) 1597, 1516,1421, 1375, 1246, 1128, 1084 cm⁻¹.

Example 342-Ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0893] Step 1.2-{4-[(5,6-Dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

[0894] A mixture of 2-chloro-5,6-dimethyl-3-nitropyridine (Godard, A.;Rocca, P.; Pomel, V.; et al. J. Organomet. Chem., 1996, 517, 25.; Rocca,P.; Marsais, F.; Godard, A.; et al. Tetrahedron Lett., 1993, 34, 2937.,3.3 g, 17.5 mmol), 4-aminophenylethyl alcohol (3.6 g, 26.3 mmol) and2,6-lutidine (3.7 mL) in toluene (80 mL) was stirred under refluxtemperature for 19 h. The mixture was diluted with ethyl acetate (100mL) and washed with 1N aqueous NaOH (50 mL) and brine (50 mL). Theorganic layer was dried (Na₂SO₄), and concentrated. Purification byflash column chromatography on silica gel eluting with hexane/ethylacetate (1:1) to afford 1.8 g (37%) of the title compound as orangesolids: ¹H-NMR (CDCl₃) δ 8.24 (1H, br.s), 7.68 (2H, d, J=8.6 Hz), 7.24(2H, d, J=8.6 Hz), 3.88 (2H, dt, J=6.1, 7.6 Hz), 2.88 (2H, t, J=7.6 Hz),2.49 (3H, s), 2.26 (3H, s), 1.43 (1H, t, J=6.1 Hz).

[0895] Step 2.2-{4-[(3-Amino-5,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol

[0896] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{4-[(5,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1).

[0897]¹H-NMR (CDCl₃) δ 6.97 (2H, d, J=8.4 Hz), 6.92 (2H, d, J=8.4 Hz),6.71 (1H, s), 6.22 (1H, br s), 3.67 (2H, t, J=6.8 Hz), 2.68 (2H, t,J=6.8 Hz), 2.29 (3H, s), 2.12 (3H, s).

[0898] Step 32-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[0899] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-5,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 2)and propionyl chloride.

[0900]¹H-NMR (CDCl₃) δ 7.75 (1H, br.s), 7.42 (2H, d, J=8.6 Hz), 7.34(2H, d, J=8.6 Hz), 4.37 (2H, t, J=6.6 Hz), 3.05 (2H, t, J=6.6 Hz), 2.80(2H, q, J=7.6 Hz), 2.49 (3H, s), 2.38 (3H, s), 2.37-2.28 (2H, m), 1.34(3H, t, J=7.6 Hz), 1.18 (3H, t, J=7.5 Hz).

[0901] Step 4.2-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0902] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 3).

[0903] MS (ESI) m/z 296 (M+H)⁺; ¹H-NMR (CDCl₃) δ: 7.75 (1H, br.s), 7.43(2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.6 Hz), 3.92 (2H, br.t, J=6.6 Hz),2.97 (2H, t, J=6.6 Hz), 2.80 (2H, q, J=7.6 Hz), 2.49 (3H, s), 2.38 (3H,s), 1.34 (3H, t, J=7.6 Hz).

[0904] Step 5.3-[4-(2-Chloroethyl)phenyl]-2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine

[0905] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 4).

[0906]¹H-NMR (CDCl₃) δ 7.75 (1H, br.s), 7.43 (2H, d, J=8.6 Hz), 7.36(2H, d, J=8.6 Hz), 3.80 (2H, t, J=7.3 Hz), 3.18 (2H, t, J=7.3 Hz), 2.81(2H, q, J=7.6 Hz), 2.50 (3H, s), 2.38 (3H, s), 1.34 (3H, t, J=7.6 Hz).

[0907] Step 6.2-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide

[0908] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine(step 5).

[0909]¹H-NMR (CDCl₃) δ 7.75 (1H, br.s), 7.42 (2H, d, J=8.4 Hz), 7.36(2H, d, J=8.4 Hz), 3.60 (2H, t, J=7.3 Hz), 3.00 (2H, t, J=7.3 Hz), 2.80(2H, q, J=7.6 Hz), 2.49 (3H, s), 2.38 (3H, s), 1.34 (3H, t, J=7.6 Hz).

[0910] Step 7.2-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0911] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide (step 6).

[0912]¹H-NMR (CDCl₃) δ 7.76 (1H, br.s), 7.41 (2H, d, J=7.9 Hz), 7.33(2H, d, J=7.9 Hz), 3.12 (2H, t, J=6.9 Hz), 2.95 (2H, t, J=6.9 Hz), 2.79(2H, q, J=6.9 Hz), 2.47 (3H, s), 2.37 (3H, s), 1.33 (3H, t, J=6.9 Hz).

[0913] Step 8.2-Ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0914] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 7).

[0915] MS (ESI) m/z 492 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.87 (2H, d, J=8.2 Hz),7.79 (1H, s), 7.31 (2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.1 Hz), 7.15 (2H,d, J=8.1 Hz), 6.24 (1H, m), 3.51 (2H, m), 2.85 (2H, t, J=6.1 Hz), 2.66(2H, q, J=7.4 Hz), 2.39 (3H, s), 2.38 (3H, s), 2.36 (3H, s), 1.25 (3H,t, J=7.4 Hz).

Example 352-Ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,sodium salt

[0916] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(Example 34).

[0917] mp 156.0-158.5° C.; ¹H-NMR (DMSO-d₆) δ 7.58 (1H, s), 7.48 (2H, d,J=8.1 Hz), 7.19-7.13 (4H, m), 6.98 (2H, d, J=8.1 Hz), 6.01 (1H, br.s),3.15-2.98 (2H, m), 2.59-2.55 (2H, m), 2.50 (2H, q, J=7.6 Hz), 2.19 (3H,s), 2.13 (3H, s), 2.09 (3H, s), 1.01 (3H, t, J=7.6 Hz).

Example 362-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[0918] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 4 of Example 34).

[0919] MS (ESI) m/z 493 (M+H)⁺; ¹H-NMR (DMSO-d₆) δ 7.94 (2H, d, J=8.4Hz), 7.78 (1H, s), 7.33 (2H, d, J=8.1 Hz), 7.25-7.16 (4H, m), 4.35 (2H,t, J=6.6 Hz), 2.93 (2H, t, J=6.6 Hz), 2.73 (2H, q, J=7.4 Hz), 2.46 (3H,s), 2.43 (3H, s), 2.39 (3H, s), 1.28 (3H, t, J=7.4 Hz).

Example 375,6-Dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0920] Step 1.2-{4-[(5,6-Dichloro-3-nitro-2-pyridinyl)amino]phenyl}ethanol

[0921] The title compound was prepared according to the proceduredescribed in step 1 of Example 34 from 3-nitro-2,5,6-trichloropyridine(Horn, U.; Mutterer, F.; Weis, C. D. Helv. Chim. Acta., 1976, 59, 190.)and 4-aminophenylethyl alcohol.

[0922] MS (EI) m/z 327 (M⁺); ¹H-NMR (CDCl₃) δ 10.11 (1H, br.s), 8.58(1H, s), 7.57 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 3.93-3.86 (2H,m), 2.89 (2H, t, J=6.6 Hz).

[0923] Step 2.2-{4-[(3-Amino-5,6-dichloro-2-pyridinyl)amino]phenyl}ethanol

[0924] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{4-[(5,6-dichloro-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1).

[0925] MS (EI) m/z 297 (M⁺).

[0926] Step 32-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[0927] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-5,6-dichloro-2-pyridinyl)amino]phenyl}ethanol (step 2)and propionyl chloride.

[0928] TLC Rf=0.63 (ethyl acetate/hexane=1:1).

[0929] Step 4.2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0930] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 3).

[0931] MS (EI) m/z 335 (M⁺); ¹H-NMR (CDCl₃) δ 8.11 (1H, s), 7.46 (2H, d,J=8.1 Hz), 7.32 (2H, d, J=8.1 Hz), 3.97 (2H, t, J=6.2 Hz), 2.99 (2H, t,J=6.2 Hz), 2.82 (2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz).

[0932] Step 5.3-[4-(2-Chloroethyl)phenyl]-2-ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridine

[0933] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 4).

[0934]¹H-NMR (CDCl₃) δ 8.13 (1H, s), 7.45 (2H, d, J=8.1 Hz), 7.33 (2H,d, J=8.1 Hz), 3.80 (2H, t, J=7.2 Hz), 3.19 (2H, t, J=7.2 Hz), 2.82 (2H,q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz).

[0935] Step 6.2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide

[0936] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridine(step 5).

[0937] MS (EI) m/z 360 (M⁺); ¹H-NMR (CDCl₃) δ 8.11 (1H, s), 7.44 (2H, d,J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 3.61 (2H, t, J=7.2 Hz), 3.00 (2H, t,J=7.2 Hz), 2.81 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.5 Hz).

[0938] Step 7.2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine

[0939] To a solution of2-[4-(2-ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide (step 6, 69 mg, 0.2 mmol) in methanol (10 mL) was added Lindlarcatalyst (5 mg). The resulting mixture was stirred for 6 h underhydrogen atmosphere. The mixture was filtered through a pad of Celiteand the filtrate was concentrated. Purification by preparative TLC(dichloromethane/methanol=10:1) gave 60 mg (94%) of the title compoundas colorless solids: MS (EI) m/z 334 (M⁺); ¹H-NMR (CDCl₃) δ 8.11 (1H,s), 7.43 (2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz), 3.11 (2H, t, J=6.6Hz), 2.92 (2H, t, J=6.6 Hz), 2.81 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.5Hz).

[0940] Step 8.5,6-Dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0941] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 7).

[0942] mp 188.0-189.0° C.; MS (ESI) m/z 532 (M+H)⁺; ¹H-NMR (CDCl₃) δ8.12 (1H, s), 7.77 (2H, d, J=8.4 Hz), 7.36-7.25 (6H, m), 6.49 (1H, br.t,J=5.9 Hz), 3.54 (2H, dt, J=5.9, 7.0 Hz), 2.90 (2H, t, J=7.0 Hz), 2.78(2H, q, J=7.5 Hz), 2.41 (3H, s), 1.33 (3H, t, J=7.5 Hz).

Example 385-Chloro-2-ethyl-6-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0943] Step 1.2-{4-[(6-Chloro-5-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

[0944] The title compound was prepared according to the proceduredescribed in step 1 of Example 34 from2,6-dichloro-5-methyl-3-nitropyridine (Horn, U.; Mutterer, F.; Weis, C.D. Helv. Chim. Acta., 1976, 59, 190.) and 4-aminophenylethyl alcohol.

[0945]¹H-NMR (CDCl₃) δ 10.05 (1H, br.s), 8.34 (1H, s), 7.57 (2H, d,J=7.7 Hz), 7.24 (2H, d, J=7.7 Hz), 3.86 (2H, t, J=5.9 Hz), 2.87 (2H, t,J=5.9 Hz), 2.33 (3H, s).

[0946] Step 2.2-{4-[(3-Amino-6-chloro-5-methyl-2-pyridinyl)amino]phenyl}ethanol

[0947] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{4-[(6-chloro-5-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step1).

[0948]¹H-NMR (CDCl₃) δ 7.14-7.08 (4H, m), 6.86 (1H, s), 6.21 (1H, br.s),3.79 (2H, t, J=6.4 Hz), 2.78 (2H, t, J=6.4 Hz), 2.33 (3H, s).

[0949] Step 3.2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[0950] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-6-chloro-5-methyl-2-pyridinyl)amino]phenyl}ethanol (step2) and propionyl chloride.

[0951] MS (EI) m/z 371 (M⁺).

[0952] Step 4.2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0953] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5-chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 3).

[0954] MS (EI) m/z 315 (M⁺); ¹H-NMR (CDCl₃) δ 7.87 (1H, s), 7.42 (2H, d,J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 3.92 (2H, t, J=6.6 Hz), 2.96 (2H, t,J=6.6 Hz), 2.79 (2H, q, J=7.7 Hz), 2.47 (3H, s), 1.34 (3H, t, J=7.7 Hz).

[0955] Step 5.3-[4-(2-Chloroethyl)phenyl]-5-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine

[0956] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(5-chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 4).

[0957] MS (EI) m/z 333 (M⁺); ¹H-NMR (CDCl₃) δ 7.88 (1H, s), 7.42 (2H, d,J=8.3 Hz), 7.33 (2H, d, J=8.3 Hz). 3.79 (2H, t, J=7.3 Hz), 3.17 (2H, t,J=7.3 Hz), 2.80 (2H, q, J=7.0 Hz), 2.48 (3H, s), 1.35 (3H, t, J=7.0 Hz).

[0958] Step 6.2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide

[0959] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from3-[4-(2-chloroethyl)phenyl]-5-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine(step 5).

[0960]¹H-NMR (CDCl₃) δ 7.87 (1H, s), 7.42 (2H, d, J=8.4 Hz), 7.34 (2H,d, J=8.4 Hz), 3.59 (2H, t, J=7.1 Hz), 2.98 (2H, t, J=7.1 Hz), 2.81 (2H,q, J=7.6 Hz), 2.48 (3H, s), 1.35 (3H, t, J=7.6 Hz).

[0961] Step 7.2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine.

[0962] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from2-[4-(5-chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide (step 6).

[0963]¹H-NMR (CDCl₃) δ 7.88 (1H, s), 7.40 (2H, d, J=8.3 Hz), 7.31 (2H,d, J=8.3 Hz), 3.07 (2H, t, J=6.8 Hz), 2.87 (2H, t, J=6.8 Hz), 2.80 (2H,q, J=7.3 Hz), 2.48 (3H, s), 1.34 (3H, t, J=7.3 Hz).

[0964] Step 8.5-Chloro-2-ethyl-6-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0965] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(5-chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 7).

[0966] mp 205-206° C.; MS (ESI) m/z 512 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.90(1H, s), 7.79 (2H, d, J=8.3 Hz), 7.33-7.23 (6H, m), 6.46 (1H, br.s),3.55-3.49 (2H, m), 2.88 (2H, t, J=6.8 Hz), 2.76 (2H, q, J=7.6 Hz), 2.48(3H, s), 2.41 (3H, s), 1.31 (3H, t, J=7.6 Hz).

Example 395-Chloro-2-ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0967] Step 1.2-{4-[(6-Chloro-4-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

[0968] The title compound was prepared according to the proceduredescribed in step 1 of Example 34 from2,6-dichloro-4-methyl-3-nitropyridine (Inubushi, A.; Kawano, E.;Shimada, Ke.; et al. PCT Int. Appl., WO 9802442 (1998)) and4-aminophenylethyl alcohol.

[0969]¹H-NMR (CDCl₃) δ: 9.56 (1H, s), 7.49 (2H, d, J=8.4 Hz), 7.22 (2H,d, J=8.4 Hz), 6.64 (1H, s), 3.84 (2H, t, J=6.4 Hz), 2.84 (2H, t, J=6.4Hz), 2.55 (3H, s).

[0970] Step 2.2-{4-[(3-Amino-6-chloro-4-methyl-2-pyridinyl)amino]phenyl}ethanol

[0971] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{4-[(6-chloro-4-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step1).

[0972] MS (EI) m/z 277 (M⁺).

[0973] Step 3.2-[4-(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[0974] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-6-chloro-4-methyl-2-pyridinyl)amino]phenyl}ethanol (step2).

[0975] TLC Rf=0.46 (ethyl acetate/hexane=1:1).

[0976] Step 4.2-[4-(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol

[0977] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 3).

[0978] MS (EI) m/z 315 (M⁺); ¹H-NMR (CDCl₃) δ 7.43 (2H, d, J=8.4 Hz),7.31 (2H, d, J=8.4 Hz), 7.07 (1H, s), 4.00-3.85 (2H, m), 2.97 (2H, t,J=6.6 Hz), 2.83 (2H, q, J=7.5 Hz), 2.68 (3H, s), 1.30 (3H, t, J=7.5 Hz).

[0979] Step 5.3-[4-(2-Chloroethyl)phenyl]-5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine

[0980] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 4).

[0981]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.1 Hz), 7.33 (2H, d, J=8.1 Hz),7.07 (1H, s), 3.79 (2H, t, J=7.3 Hz), 3.17 (2H, t, J=7.3 Hz), 2.83 (2H,q, J=7.5 Hz), 2.68 (3H, s), 1.30 (3H, t, J=7.5 Hz).

[0982] Step 6.2-[4-(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide

[0983] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from3-[4-(2-chloroethyl)phenyl]-5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine(step 5).

[0984]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.6 Hz),7.07 (1H, s), 3.56 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 2.83 (2H,q, J=7.5 Hz), 2.68 (3H, s), 1.29 (3H, t, J=7.5 Hz).

[0985] Step 7.2-[4-(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine.

[0986] To a stirred solution of2-[4-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide (step 6, 57 mg, 0.2 mmol) in THF (5 mL) was addedtriphenylphosphine (47 mg, 0.2 mmol) at room temperature. Aftercompletion of the addition, the stirring was continued for an additional3 h at the same temperature. To the resulting mixture was added water(0.1 mL) at room temperature, and the reaction mixture was stirred atroom temperature for 20 h. The mixture was concentrated to givecolorless solids. Purification by preparative TLC(dichloromethane/methanol/triethylamine=10:1:1) gave 13 mg (25%) of thetitle compound as colorless solids: MS (EI) m/z 313 (M⁺).

[0987] Step 8.5-Chloro-2-ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[0988] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 7).

[0989] MS (ESI) m/z 512 (M+H)⁺; ¹H-NMR (CDCl₃) δ: 7.80 (2H, d, J=8.4Hz), 7.34-7.23 (6H, m), 7.09 (1H, s), 6.37 (1H, br s), 3.56-3.52 (2H,m), 2.88 (2H, t, J=6.8 Hz), 2.77 (2H, q, J=7.5 Hz), 2.69 (3H, s), 2.42(3H, s), 1.26 (3H, t, J=7.5 Hz).

Example 402-Ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-6-[(methylsulfonyl)amino]-3H-imidazo[4,5-b]pyridine

[0990] Step 1.2-{4-[(4-Methyl-3,5-dinitro-2-pyridinyl)amino]phenyl}ethanol

[0991] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from2-chloro-4-methyl-3,5-dinitropyridine. (Czuba, Rocz.Chem., 1967, 41,479) and 4-aminophenylethyl alcohol.

[0992]¹H-NMR (CDCl₃) δ 8.90 (1H, s), 8.50 (1H, br.s), 7.40 (2H, d, J=8.4Hz), 7.23 (2H, d, J=8.4 Hz), 3.82 (2H, t, J=6.6 Hz), 2.84 (2H, t, J=6.6Hz), 2.62 (3H, s).

[0993] Step 2.2-{4-[(3-Amino-4-methyl-5-nitro-2-pyridinyl)amino]phenyl}ethanol

[0994] To a stirred solution of2-{4-[(4-methyl-3,5-dinitro-2-pyridinyl)amino]phenyl}ethanol (step 1,4.2 g, 13.1 mmol), triethylamine (9.6 mL, 68.9 mmol), 10% Pd—C (624 mg,0.59 mmol) in acetonitrile (14 mL) was added dropwise a solution offormic acid (2.3 mL, 61.0 mmol) in acetonitrile (6.2 mL) at 0° C. over aperiod of 30 min. After stirring at room temperature for 5 h, themixture was filtered through a pad of Celite, and the filtrate wasconcentrated. The residue was dissolved in dichloromethane (100 mL). Thesolution was washed with 1N aqueous NaOH (50 mL), brine (50 mL), dried(MgSO₄), and concentrated. Purification by flash column chromatographyon silica gel eluting with hexane/ethyl acetate (gradient elution from1:1 to 1:2) afforded 2.2 g (60%) of the title compound as red crystals:¹H-NMR (CDCl₃) δ 8.42 (1H, s), 7.42 (2H, d, J=8.4 Hz), 7.21 (2H, d,J=8.4 Hz), 6.7 (1H, br s), 3.85 (2H, t, J=6.4 Hz), 2.86 (2H, t, J=6.6Hz), 2.47 (3H, s).

[0995] Step 3.2-[4-(2-Ethyl-7-methyl-6-nitro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[0996] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(3-amino-4-methyl-5-nitro-2-pyridinyl)amino]phenyl}ethanol (step2) and propionyl chloride.

[0997]¹H-NMR (CDCl₃) δ 9.03 (1H, s), 7.48 (2H, d, J=8.6 Hz), 7.33 (2H,d, J=8.4 Hz), 4.38 (2H, t, J=6.9 Hz), 3.07 (2H, t, J=6.9 Hz), 3.03 (3H,s), 2.87 (2H, q, J=7.6 Hz), 2.35 (2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.4Hz), 1.13 (3H, t, J=7.4 Hz).

[0998] Step 4.2-[4-(6-Amino-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[0999] A suspension of2-[4-(2-ethyl-7-methyl-6-nitro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 3, 2.5 g, 6.6 mmol), 10% Pd—C (250 mg, 0.23 mmol) inmethanol (100 mL) was stirred under hydrogen atmosphere for 2 h. Thesuspension was filtered through a pad of Celite, and the filtrate wasconcentrated to afford 2.4 g (99%) of the title compound as a brown oil:¹H-NMR (CDCl₃) δ 7.82 (1H, s), 7.41 (2H, d, J=8.2 Hz), 7.32 (2H, d,J=8.4 Hz), 4.35 (2H, t, J=7.0 Hz), 3.51 (2H, br.s), 3.03 (2H, t, J=7.0Hz), 2.82 (2H, q, J=7.5 Hz), 2.53 (3H, s), 2.35 (2H, q, J=7.5 Hz), 1.29(3H, t, J=7.5 Hz), 1.44 (3H, t, J=7.5 Hz).

[1000] Step 5.2-(4-{2-Ethyl-7-methyl-6-[(methylsulfonyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethylpropionate

[1001] To a stirred solution of2-[4-(6-amino-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 4, 1.0 g, 3.0 mmol) and pyridine (280 mg, 3.5 mmol) indichloromethane (18 mL) was added methanesulfonyl chloride (372 mg, 3.3mmol) at 0° C., and the mixture was stirred at room temperature for 16h. The reaction was quenched with water (10 mL), and the mixture wasextracted with dichloromethane (50 mL). The organic layer was washedwith brine (50 mL), dried (MgSO₄), and concentrated. Purification byflash column chromatography on silica gel eluting with ethyl acetate(gradient elution from 1:1 to 1:2) afforded 890 mg (70%) of the titlecompound as an amber oil: ¹H-NMR (CDCl₃) δ 8.26 (1H, s), 7.43 (2H, d,J=8.4 Hz), 7.32 (2H, d, J=8.2 Hz), 7.00 (1H, br.s), 4.35 (2H, t, J=7.0Hz), 3.03-3.01 (5H, m), 2.85 (2H, q, J=7.5 Hz), 2.75 (3H, s), 2.35 (2H,q, J=7.5 Hz), 1.30 (3H, t, J=7.5 Hz), 1.14 (3H, t, J=7.5 Hz).

[1002] Step 6.N-{2-Ethyl-3-[4-(2-hydroxyethyl)phenyl]-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide

[1003] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-(4-{2-ethyl-7-methyl-6-[(methylsulfonyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethylpropionate (step 5).

[1004]¹H-NMR (CDCl₃) δ 8.22 (1H, s), 7.46 (2H, d, J=8.2 Hz), 7.31 (2H,d, J=8.4 Hz), 6.52 (1H, br.s), 3.93 (2H, t, J=6.6 Hz), 3.03 (3H, s),2.97 (2H, t, J=6.6 Hz), 2.85 (2H, q, J=7.6 Hz), 2.76 (3H, s), 1.32 (3H,t, J=7.4 Hz).

[1005] Step 7.N-{3-[4-(2-Chloroethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide

[1006] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 fromN-{2-ethyl-3-[4-(2-hydroxyethyl)phenyl]-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide(step 6).

[1007] TLC Rf=0.40 (ethyl acetate).

[1008] Step 8.N-{3-[4-(2-Azidoethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide

[1009] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 fromN-{3-[4-(2-chloroethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide(step 7).

[1010]¹H-NMR (CDCl₃) δ 8.26 (1H, s), 7.44 (2H, d, J=8.1 Hz), 7.34 (2H,d, J=8.1 Hz), 6.65 (1H, br.s), 3.59 (2H, t, J=7.0 Hz), 3.03 (3H, s),2.99 (2H, t, J=7.1 Hz), 2.86 (2H, q, J=7.4 Hz), 2.75 (3H, s), 1.31 (3H,t, J=7.5 Hz).

[1011] Step 9.N-{3-[4-(2-Aminoethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide

[1012] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 fromN-{3-[4-(2-azidoethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide(step 8).

[1013] TLC Rf=0.05 (ethyl acetate).

[1014] Step 10.2-Ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-6-[(methylsulfonyl)amino]-3H-imidazo[4,5-b]pyridine

[1015] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 fromN-{3-[4-(2-aminoethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide(step 9).

[1016] mp 166° C.; MS (ESI) m/z 571.25 (M+H)⁺; ¹H-NMR (CDCl₃) δ 8.16(1H, s), 7.81 (2H, d, J=8.1 Hz), 7.31-7.18 (6H, m), 6.39 (1H, br.s),3.48-3.46 (2H, m), 3.00 (3H, s), 2.82-2.71 (7H, m), 2.39 (3H, s), 1.26(3H, t, J=7.2 Hz).

Example 416-Cyano-2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[1017] Step 1,6-Hydroxy-2,4-dimethylnicotinonitrile

[1018] To a stirred solution of 6-amino-2,4-dimethylnicotinonitrile(Sato, K.; et al. Bull.Chem.Soc.Jpn., 1969, 42, 2319., 22.4 g, 152 mmol)in 5% aqueous sulfuric acid (600 mL) was added dropwise a solution ofsodium nitrite (25.2 g, 365 mmol) in water (100 mL) at 0° C., and themixture was stirred at room temperature for 16 h. The resultingprecipitate was collected by filtration to afford 10.2 g (45%) of thetitle compound: ¹H-NMR (DMSO-d₆) δ 12.27 (1H, br.s), 6.17 (1H, s), 2.38(3H, s), 2.20 (3H, s).

[1019] Step 2. 6-Hydroxy-2,4-dimethyl-5-nitronicotinonitrile

[1020] To a stirring mixture of nitric acid (fuming, 36 mL) and sulfuricacid (18 mL) was added 6-hydroxy-2,4-dimethylnicotinonitrile (step 1,9.0 g, 60.8 mmol) in one portion, and the mixture was stirred at roomtemperature. After 1 h, the mixture was poured in water (100 mL) andneutralized with 2N aqueous NaOH. The resulting precipitates werecollected by filtration to afford 3.2 g (27%) of the title compound:¹H-NMR (DMSO-d₆) δ 2.28 (3H, s), 2.11 (3H, s).

[1021] Step 3. 6-Chloro-2,4-dimethyl-5-nitronicotinonitrile

[1022] A mixture of 6-hydroxy-2,4-dimethyl-5-nitronicotinonitrile (step2, 3.2 g, 16.6 mmol) and phosphorus oxychloride (20 mL) was stirred at100° C. for 16 h. After cooling, the mixture was poured in water (100mL). The resulting mixture was extracted with dichloromethane (3×100mL). The organic layer was washed with brine (50 mL), dried (MgSO₄), andconcentrated to afford 2.3 g (66%) of the title compound as brownsolids: ¹H-NMR (DMSO-d₆) δ 2.82 (3H, s), 2.52 (3H, s).

[1023] Step 4.6-[4-(2-Hydroxyethyl)anilino]-2,4-dimethyl-5-nitronicotinonitrile

[1024] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from6-chloro-2,4-dimethyl-5-nitronicotinonitrile (step 3) and4-aminophenylethyl alcohol.

[1025]¹H-NMR (CDCl₃) δ 9.37 (1H, br.s), 7.51 (2H, d, J=8.4 Hz), 7.26(2H, d, J=8.4 Hz), 3.89-3.87 (2H, m), 2.89 (2H, t, J=6.4 Hz), 2.72 (3H,s), 2.65 (3H, s), 1.46 (1H, t, J=5.8 Hz).

[1026] Step 5.5-Amino-6-[4-(2-hydroxyethyl)anilino]-2,4-dimethylnicotinonitrile

[1027] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from6-[4-(2-hydroxyethyl)anilino]-2,4-dimethyl-5-nitronicotinonitrile (step4).

[1028]¹H-NMR (CDCl₃) δ 7.49 (2H, d, J=8.6 Hz), 7.19 (2H, d, J=8.4 Hz),6.98 (1H, br.s), 3.89-3.82 (2H, m), 3.11 (2H, br.s), 2.85 (2H, t, J=6.6Hz), 2.58 (3H, s), 2.38 (3H, s), 1.44 (1H, t, J=5.6 Hz).

[1029] Step 6.2-[4-(6-Cyano-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate

[1030] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from5-amino-6-[4-(2-hydroxyethyl)anilino]-2,4-dimethylnicotinonitrile (step5) and propionyl chloride.

[1031] TLC Rf=0.4 (hexane/ethyl acetate=1:1).

[1032] Step 7.2-Ethyl-3-[4-(2-hydroxyethyl)phenyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile

[1033] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(6-cyano-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylpropionate (step 6).

[1034]¹H-NMR (CDCl₃) δ 7.46 (2H, d, J=8.2 Hz), 7.31 (2H, d, J=8.2 Hz),4.01-3.94 (2H, m), 3.49-3.47 (1H, m), 3.00 (2H, t, J=6.3 Hz), 2.86 (3H,s), 2.83 (2H, q, J=7.4 Hz), 2.74 (3H, s), 1.32 (3H, t, J=7.6 Hz).

[1035] Step 8.3-[4-(2-Chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile

[1036] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-ethyl-3-[4-(2-hydroxyethyl)phenyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile(step 7).

[1037] TLC Rf=0.8 (hexane/ethyl acetate=1:1).

[1038] Step 9.3-[4-(2-Azidoethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile

[1039] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile(step 8).

[1040]¹H-NMR (CDCl₃) δ 7.46 (2H, d, J=8.1 Hz), 7.33 (2H, d, J=8.2 Hz),3.62 (2H, t, J=7.1 Hz), 3.02 (2H, t, J=7.1 Hz), 2.86 (3H, s), 2.82 (2H,q, J=7.6 Hz), 2.73 (3H, s), 1.31 (3H, t, J=7.6 Hz).

[1041] Step 10.3-[4-(2-Aminoethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile

[1042] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from3-[4-(2-azidoethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile(step 9).

[1043] TLC Rf=0.05 (hexane/ethyl acetate=1:1).

[1044] Step 11.6-Cyano-2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[1045] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from3-[4-(2-aminoethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile(step 10).

[1046] mp 133° C.; MS (ESI) m/z 517.12 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.78(2H, d, J=8.1 Hz), 7.37-7.25 (6H, m), 6.46 (1H, br.s), 3.56-3.54 (2H,m), 2.92 (2H, t, J=7.0 Hz), 2.85 (3H, s), 2.76 (2H, q, J=6.0 Hz), 2.68(3H, s), 2.41 (3H, s), 1.29 (3H, t, J=6.2 Hz).

Example 422-Ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-c]pyridine

[1047] Step 1.2-{4-[(2,6-Dimethyl-3-nitro-4-pyridinyl)amino]phenyl}ethanol

[1048] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from4-chloro-2,6-dimethyl-3-nitropyridine (Tanaka, A.; et al. J.Med.Chem.,1999, 41, 4408.) and 4-aminophenylethyl alcohol.

[1049]¹H-NMR (CDCl₃) δ 8.74 (1H, br.s), 7.31 (2H, d, J=8.2 Hz), 7.18(2H, d, J=8.2 Hz), 6.68 (1H, s), 3.95-3.89 (2H, m), 2.91 (2H, t, J=6.6Hz), 2.72 (3H, s), 2.36 (3H, s).

[1050] Step 2.2-{4-[(3-Amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol

[1051] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from2-{4-[(2,6-dimethyl-3-nitro-4-pyridinyl)amino]phenyl}ethanol (step 1).

[1052]¹H-NMR (CDCl₃) δ 7.19 (2H, d, J=8.4 Hz), 7.01 (2H, d, J=8.6 Hz),6.76 (1H, s), 5.82 (1H, br.s), 3.87 (2H, t, J=6.4 Hz), 3.18 (2H, br.s),2.85 (2H, t, J=6.4 Hz), 2.44 (3H, s), 2.35 (3H, s).

[1053] Step 3.2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylpropionate

[1054] A mixture of2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2,2.4 g, 9.3 mmol), propionic anhydride (13 mL, 101 mmol) and propionicacid (13 mL, 174 mmol) was stirred at 120° C. for 16 h. After cooling,the mixture was diluted with 2N aqueous NaOH (150 mL) and extracted withdichloromethane (3×150 mL). The combined organic extracts were washedwith brine (50 mL), dried (MgSO₄), and concentrated. Purification byflash column chromatography on silica gel eluting withdichloromethane/methanol (gradient elution from 20:1 to 10:1) afforded2.3 g (69%) of the title compound as a brown oil: ¹H-NMR (CDCl₃) δ 7.44(2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.2 Hz), 6.72 (1H, s), 4.38 (2H, t,J=6.9 Hz), 3.07 (2H, t, J=7.1 Hz), 2.88 (3H, s), 2.82 (2H, q, J=7.6 Hz),2.56 (3H, s), 2.36 (2H, q, J=7.6 Hz), 1.29 (3H, t, J=7.6 Hz), 1.15 (3H,t, J=7.7 Hz).

[1055] Step 4.2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol

[1056] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylpropionate (step 3).

[1057]¹H-NMR (CDCl₃) δ 7.46 (2H, d, J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz),6.73 (1H, s), 4.00 (2H, t, J=6.6 Hz), 3.01 (2H, t, J=6.4 Hz), 2.88 (3H,s), 2.81 (2H, q, J=7.5 Hz), 2.54 (3H, s), 1.29 (3H, t, J=7.5 Hz).

[1058] Step 5.1-[4-(2-Chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine

[1059] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol(step 4).

[1060] TLC Rf=0.1 (ethyl acetate).

[1061] Step 6.1-[4-(2-Azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine

[1062] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine(step 5).

[1063]¹H-NMR (CDCl₃) δ 7.46 (2H, d, J=8.0 Hz), 7.29 (2H, d, J=7.7 Hz),6.72 (1H, s), 3.62 (2H, t, J=6.9 Hz), 3.02 (2H, t, J=6.9 Hz), 2.88 (3H,s), 2.81 (2H, q, J=7.4 Hz), 2.56 (3H, s), 1.29 (3H, t, J=7.6 Hz).

[1064] Step 7.2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylamine

[1065] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from1-[4-(2-azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine(step 6).

[1066]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.2 Hz), 7.26 (2H, d, J=8.4 Hz),6.73 (1H, s), 3.08 (2H, t, J=6.9 Hz), 2.90-2.78 (4H, m), 2.88 (3H, s),2.56 (3H, s), 1.30 (3H, t, J=7.3 Hz).

[1067] Step 8.2-Ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine

[1068] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylamine(step 7).

[1069] mp 143° C.; MS (ESI) m/z 492.12 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.77(2H, d, J=8.3 Hz), 7.38 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.20(2H, d, J=8.4 Hz), 6.77 (1H, s), 3.58-3.51 (2H, m), 2.92 (2H, t, J=7.0Hz), 2.89 (3H, s), 2.79 (2H, q, J=7.5 Hz), 2.53 (3H, s), 2.38 (3H, s),1.28 (3H, t, J=7.5 Hz).

Example 432-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1070] Step 1. 2-[4-(2-Nitroanilino)phenyl]ethanol

[1071] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2-chloronitrobenzene and4-aminophenylethyl alcohol.

[1072]¹H-NMR (CDCl₃) δ 9.47 (1H, s), 8.21 (1H, dd, J=1.5, 8.8 Hz),7.40-7.16 (6H, m), 6.81-6.70 (1H, m), 3.91 (2H, t, J=6.5 Hz), 2.90 (2H,t, J=6.5 Hz).

[1073] Step 2. 2-[4-(2-Aminoanilino)phenyl]ethanol

[1074] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from2-[4-(2-nitroanilino)phenyl]ethanol (step 1).

[1075]¹H-NMR (CDCl₃) δ 7.15-6.96 (4H, m), 6.82-6.66 (4H, m), 5.14 (1H,s), 3.80 (2H, t, J=6.6 Hz), 3.75 (2H, br.s), 2.79 (2H, t, J=6.6 Hz).

[1076] Step 3. 2-[4-(2-Ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1077] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-aminoanilino)phenyl]ethanol (step 2) and propionyl chloride.

[1078] MS (EI) m/z 322 (M⁺); ¹H-NMR (CDCl₃) δ 7.79 (1H, d, J=7.7 Hz),7.43 (2H, d, J=8.6 Hz), 7.34-7.06 (5H, m), 4.38 (2H, t, J=7.0 Hz), 3.07(2H, t, J=7.0 Hz), 2.80 (2H, q, J=7.5 Hz), 2.36 (2H, q, J=7.6 Hz), 1.35(3H, t, J=7.5 Hz), 1.15 (3H, t, J=7.6 Hz).

[1079] Step 4. 2-[4-(2-Ethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1080] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step 3).

[1081]¹H-NMR (CDCl₃) δ 7.81-7.75 (1H, m), 7.45 (2H, d, J=8.3 Hz), 7.31(2H, d, J=8.3 Hz), 7.25-7.08 (3H, m), 3.98 (2H, t, J=6.5 Hz), 3.00 (2H,t, J=6.5 Hz), 2.80 (2H, q, J=7.5 Hz), 1.26 (3H, t, J=7.5 Hz).

[1082] Step 5. 2-[4-(2-Ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide

[1083] The title compound was prepared according to the proceduredescribed in step 5 Example 26 from2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1084] MS (EI) m/z 291 (M⁺); ¹H-NMR (CDCl₃) δ 7.81-7.76 (1H, m), 7.43(2H, d, J=8.3 Hz), 7.40-7.06 (5H, m), 3.62 (2H, t, J=6.5 Hz), 3.04 (2H,t, J=6.5 Hz), 2.80 (2H, q, J=7.5 Hz), 1.27 (3H, t, J=7.5 Hz).

[1085] Step 6. 2-[4-(2-Ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1086] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 5).

[1087]¹H-NMR (CDCl₃) δ 7.80-7.74 (1H, m), 7.45-7.06 (7H, m), 3.06 (2H,t, J=6.5 Hz), 2.89 (2H, t, J=6.5 Hz), 2.76 (2H, q, J=7.5 Hz), 1.26 (3H,t, J=7.5 Hz).

[1088] Step 7.2-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1089] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 6).

[1090]¹H-NMR (CDCl₃) δ 7.75 (1H, d, J=8.8 Hz), 7.71 (2H, d, J=8.3 Hz),7.39-7.14 (8H, m), 7.07 (1H, d, J=8.8 Hz), 6.68 (1H, br.s), 3.62-3.54(2H, m), 2.94 (2H, t, J=6.3 Hz), 2.79 (2H, q, J=7.0 Hz), 2.41 (3H, s),1.33 (3H, t, J=7.0 Hz).

Example 44 2-[4-(2-Ethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[1091] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 of Example43).

[1092]¹H-NMR (CDCl₃) δ 7.93 (2H, d, J=8.3 Hz), 7.85-7.75 (2H, m),7.40-7.15 (7H, m), 7.08 (1H, d, J=8.8 Hz), 4.77 (1H, br.s) 4.36 (2H, t,J=6.4 Hz), 3.00 (2H, t, J=6.4 Hz), 2.78 (2H, q, J=7.0 Hz), 2.44 (3H, s),1.32 (3H, t, J=7.0 Hz).

Example 454-Methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1093] Step 1. 2-[4-(3-Methyl-2-nitroanilino)phenyl]ethanol

[1094] A mixture of 2-nitro-3-methylaniline (Newman, M. S.; Kannan R. J.Org. Chem., 1976, 41, 3356., 1.9 g, 12.4 mmol), 4-bromophenylethylalcohol (2.5 g, 12.4 mmol), K₂CO₃ (1.7 g, 12.4 mmol) and CuI (230 mg,1.24 mmol) was placed in a sealed tube and heated at 200° C. for 2 h.After cooling, the mixture was poured into water (100 mL) and extractedwith ethyl acetate (300 mL). The organic layer was washed with 2Naqueous NaOH (100 mL) and brine (100 mL), then dried (Na₂SO₄), andconcentrated. Purification by flash column chromatography on silica geleluting with hexane/ethyl acetate (1:1) to afford 700 mg (21%) of thetitle compound as an orange oil: ¹H-NMR (CDCl₃) δ 7.77 (1H, br.s),7.09-7.45 (6H, m), 6.69 (1H, d, J=6.3 Hz), 3.83 (2H, t, J=6.6 Hz), 2.82(2H, t, J=6.6 Hz), 2.59 (3H, s).

[1095] Step 2. 2-[4-(2-Amino-3-methylanilino)phenyl]ethanol

[1096] The title compound was prepared according to the proceduredescribed in step 2 of Example 26 from2-[4-(3-methyl-2-nitroanilino)phenyl]ethanol (step 1).

[1097]¹H-NMR (CDCl₃) δ 7.02 (2H, d, J=8.2 Hz), 6.95 (1H, d, J=7.7 Hz),6.91 (1H, d, J=7.0 Hz), 6.65 (1H, dd, J=7.0 Hz, 7.7 Hz), 6.62 (2H, d,J=8.2 Hz), 5.15 (1H, br.s), 3.75 (2H, t, J=6.6 Hz), 2.73 (2H, t, J=6.6Hz), 2.19 (3H, s).

[1098] Step 3. 2-[4-(2-Ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1099] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-3-methylanilino)phenyl]ethanol (step 2) and propionylchloride.

[1100] TLC Rf=0.6 (hexane:ethyl acetate=1:1).

[1101] Step 4.2-[4-(2-Ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1102] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1103]¹H-NMR (CDCl₃) δ 7.41-7.43 (2H, m), 7.29 (2H, d, J=6.4 Hz), 7.07(2H, d, J=6.4 Hz), 6.91-6.94 (1H, m), 3.97 (2H, t, J=6.6 Hz), 2.99 (2H,t, J=6.6 Hz), 2.84 (2H, q, J=7.5 Hz), 2.71 (3H, s), 1.27 (3H, t, J=7.5Hz).

[1104] Step 5.1-[4-(2-Chloroethyl)phenyl]-2-ethyl-4-methyl-1H-benzimidazole

[1105] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1106]¹H-NMR (CDCl₃) δ 7.43 (2H, d, J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz),7.07-7.09 (2H, m), 6.90-6.95 (1H, m), 3.81 (2H, t, J=7.2 Hz), 3.19 (2H,t, J=7.2 Hz), 2.84 (2H, q, J=7.5 Hz), 2.72 (3H, s), 1.27 (3H, t, J=7.5Hz).

[1107] Step 6. 2-[4-(2-Ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1108] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-4-methyl-1H-benzimidazole (step 5).

[1109]¹H-NMR (CDCl₃) δ 7.43 (2H, d, J=8.0 Hz), 7.31 (2H, d, J=8.0 Hz),7.05-7.09 (2H, m), 6.90-6.94 (1H, m), 3.61 (2H, t, J=7.0 Hz), 3.01 (2H,t, J=7.0 Hz), 2.84 (2H, q, J=7.5 Hz), 2.72 (3H, s), 1.27 (3H, t, J=7.5Hz).

[1110] Step 7.2-[4-(2-Ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1111] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 6).

[1112]¹H-NMR (CDCl₃) δ 7.40 (2H, d, J=8.3 Hz), 7.28 (2H, d, 8.3 Hz),7.04-7.11 (2H, m), 6.86-6.95 (1H, m), 3.07 (2H, t, J=6.6 Hz), 2.87 (2H,t, J=6.6 Hz), 2.84 (2H, q, J=7.5 Hz), 2.71 (3H, s), 1.27 (3H, t, J=7.5Hz).

[1113] Step 8.2-Ethyl-4-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1114] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 7).

[1115] MS (ESI) m/z 477 (M+H)⁺; ¹H-NMR (DMSO-d₆) δ 7.65 (2H, d, J=7.7Hz), 7.33-7.41 (4H, m), 7.15 (2H, d, J=7.7 Hz), 7.01-7.07 (2H, m), 6.86(1H, d, J=6.8 Hz), 3.19 (2H, br.s), 2.68-2.74 (4H, m), 2.56 (3H, s),2.28 (3H, s), 1.21 (3H, t, J=7.1 Hz); IR (KBr) ν_(max) 3390, 1602, 1519,1429, 1230, 1130, 1085 cm⁻¹.

Example 464-Methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1116] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-4-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 45).

[1117]¹H-NMR (DMSO-d₆) δ 7.65 (2H, d, J=7.7 Hz), 7.33-7.41 (4H, m), 7.15(2H, d, J=7.7 Hz), 7.01-7.07 (2H, m), 6.86 (1H, d, J=6.8 Hz), 3.19 (2H,br.s), 2.68-2.74 (4H, m), 2.56 (3H, s), 2.28 (3H, s), 1.21 (3H, t, J=7.1Hz); IR (KBr) ν_(max) 3390, 1602, 1519, 1429, 1230, 1130, 1085 cm⁻¹.

Example 472-Ethyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1118] Step 1. 2-[(4-Methyl-2-nitroanilino)phenyl]ethanol

[1119] The title compound was prepared according to the proceduredescribed in step 1 Example 45 from 4-methyl-2-nitroaniline and4-iodophenylethyl alcohol.

[1120]¹H-NMR (CDCl₃) δ 9.35 (1H, br.s), 8.00 (1H, s), 7.33-7.09 (6H, m),3.91-3.89 (2H, m), 2.89 (2H, t, J=6.4 Hz), 2.30 (3H, s).

[1121] Step 2. 2-[(2-Amino-4-methylanilino)phenyl]ethanol

[1122] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[(4-methyl-2-nitroanilino)phenyl]ethanol (step 1).

[1123]¹H-NMR (CDCl₃) δ 7.05 (2H, d, J=8.3 Hz), 6.98 (1H, d, J=7.7 Hz),6.67-6.64 (3H, m), 6.58-6.55 (1H, m), 5.06 (1H, br.s), 3.80-3.78 (4H,m), 2.77 (2H, t, J=6.4 Hz), 2.28 (3H, s).

[1124] Step 3. 2-[4-(2-Ethyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1125] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[(2-amino-4-methylanilino)phenyl]ethanol (step 2) and propionylchloride.

[1126] TLC Rf=0.33 (hexane/ethyl acetate=2:1).

[1127] Step 4.2-[4-(2-Ethyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1128] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-Ethyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1129]¹H-NMR (CDCl₃) δ 7.55 (1H, s), 7.43 (2H, d, J=8.3 Hz), 7.28 (2H,d, J=8.3 Hz), 6.99-6.95 (2H, m), 3.99 (2H, t, J=6.6 Hz), 3.00 (2H, t,J=6.6 Hz), 2.77 (2H, q, J=7.7 Hz), 2.47 (3H, s), 1.32 (3H, t, J=7.7 Hz).

[1130] Step 5. 2-[4-(2-Ethyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1131] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-[4-(2-ethyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1132] TLC Rf=0.74 (Hexane/ethyl acetate=1:1).

[1133] Step 6.2-[4-(2-Ethyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1134] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 5).

[1135]¹H-NMR (CDCl₃) δ 7.55 (1H, s), 7.43 (2H, d, J=8.2 Hz), 7.29 (2H,d, J=8.2 Hz), 7.01-6.95 (2H, m), 4.85 (2H, br.s), 3.30-3.25 (2H, m),3.16-3.11 (2H, m), 2.76 (2H, q, J=7.6 Hz), 2.45 (3H, s), 1.31 (3H, t,J=7.6 Hz).

[1136] Step 7.2-Ethyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1137] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 6).

[1138]¹H-NMR (DMSO-d₆) δ 7.76 (2H, d, J=8.4 Hz), 7.42-7.36 (6H, m),7.00-6.91 (2H, m), 6.53-6.49 (1H, m), 3.29-3.24 (2H, m), 2.79-2.65 (4H,m), 2.40 (3H, s), 2.33 (3H, s), 1.20 (3H, t, J=7.4 Hz).

Example 482-Ethyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1139] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 47).

[1140]¹H-NMR (DMSO-d₆) δ 7.60 (2H, d, J=7.7 Hz), 7.42-7.33 (5H, m), 7.13(2H, d, J=7.7 Hz), 6.96 (2H, m), 3.16 (2H, m), 2.71-2.66 (4H, m), 2.39(3H, s), 2.27 (3H, s), 1.20 (3H, t, J=7.5 Hz); IR (KBr) ν_(max) 1599,1514, 1285, 1232, 1130, 1086 cm⁻¹.

Example 492-Butyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]butyl}phenyl)-1H-benzimidazole

[1141] Step 1. 2-[4-(2-Butyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethylpentanoate

[1142] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[(2-amino-4-methylanilino)phenyl]ethanol (step 2 of Example 47) andpentanoyl chloride.

[1143]¹H-NMR (CDCl₃) δ 7.56-7.55 (1H, m), 7.43-7.40 (2H, m), 7.29-7.26(2H, m), 7.02-6.94 (2H, m), 4.38 (2H, t, J=6.9 Hz), 3.06 (2H, t, J=6.9Hz), 2.75 (2H, t, J=7.4 Hz), 2.47 (3H, s), 2.33 (2H, t, J=7.4 Hz),1.80-1.55 (4H, m), 1.41-1.23 (4H, m), 0.94-0.83 (6H, m).

[1144] Step 2.2-[4-(2-Butyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1145] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-butyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl pentanoate(step 1).

[1146]¹H-NMR (CDCl₃) δ 7.55 (1H, s), 7.44 (2H, d, J=8.2 Hz), 7.27 (2H,d, J=8.2 Hz), 7.02-6.95 (2H, m), 3.99 (2H, t, J=6.6 Hz), 3.01 (2H, t,J=6.6 Hz), 2.75 (2H, t, J=7.3 Hz), 2.47 (3H, s), 1.79-1.68 (2H, m),1.36-1.23 (2H, m), 0.85 (3H, t, J=7.3 Hz).

[1147] Step 3. 2-[4-(2-Butyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1148] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-[4-(2-butyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 2).

[1149]¹H-NMR (CDCl₃) δ 7.56 (1H, s), 7.42 (2H, d, J=8.4 Hz), 7.29 (2H,d, J=8.4 Hz), 7.03-6.95 (2H, m), 3.61 (2H, t, J=6.9 Hz), 3.01 (2H, t,J=6.9 Hz), 2.75 (2H, t, J=7.3 Hz), 2.47 (3H, s), 1.80-1.68 (2H, m),1.37-1.26 (2H, m), 0.85 (3H, t, J=7.3 Hz).

[1150] Step 3.2-[4-(2-Butyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1151] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-butyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 2).

[1152]¹H-NMR (CDCl₃) δ 7.55 (1H, s), 7.40 (2H, d, J=8.3 Hz), 7.26 (2H,d, J=8.3 Hz), 7.01-6.94 (2H, m), 3.15 (2H, t, J=7.3 Hz), 2.98 (2H, t,J=7.3 Hz), 2.74 (2H, t, J=7.7 Hz), 2.46 (3H, s), 1.77-1.67 (2H, m),1.35-1.28 (2H, m), 0.84 (3H, t, J=7.7 Hz).

[1153] Step 4.2-Butyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1154] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-butyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 3).

[1155]¹H-NMR (CDCl₃) δ 7.76 (2H, d, J=8.2 Hz), 7.54 (1H, m), 7.31-7.21(6H, m), 7.03-6.95 (2H, m), 6.67-6.63 (1H, m), 3.61-3.54 (2H, m), 2.91(2H, t, J=7.1 Hz), 2.73 (2H, t, J=7.3 Hz), 2.47 (3H, s), 2.40 (3H, s),1.76-1.65 (2H, m), 1.36-1.28 (2H, m), 0.83 (3H, t, J=7.3 Hz).

Example 502-Butyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]butyl}phenyl)-1H-benzimidazole,sodium salt

[1156] The title compound was prepared according to the proceduredescribed in Example 2 from2-butyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 49).

[1157] mp 130-140° C.; ¹H-NMR (DMSO-d₆) δ 7.59 (2H, d, J=7.8 Hz),7.40-7.31 (5H, m), 7.11 (2H, d, J=7.8 Hz), 6.98-6.92 (2H, m), 3.15 (2H,m), 2.71-2.66 (4H, m), 2.39 (3H, s), 2.26 (3H, s), 1.67-1.57 (2H, m),1.31-1.21 (2H, m), 0.79 (3H, t, J=7.5 Hz); IR (KBr) ν_(max) 1599, 1514,1400, 1130, 1086 cm⁻¹.

Example 516-Methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1158] Step 1. 2-[4-(5-Methyl-2-nitroanilino)phenyl]ethanol

[1159] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2-fuluoro-4-methylnitrobenzene and4-aminophenylethyl alcohol.

[1160]¹H-NMR (CDCl₃) δ 9.51 (1H, br.s), 8.10 (1H, d, J=8.8 Hz),7.20-7.31 (4H, m), 6.98 (1H, s), 6.58 (1H, d, J=8.4 Hz), 3.91 (2H, t,J=6.4 Hz), 2.89 (t, J=6.4 Hz), 2.27 (3H, s).

[1161] Step 2. 2-[4-(2-Amino-5-methylanilino)phenyl]ethanol

[1162] The title compound was prepared according to the proceduredescribed in step 2 of Example 26 from2-[4-(5-methyl-2-nitroanilino)phenyl]ethanol (step 1).

[1163]¹H-NMR (CDCl₃) δ 7.07 (2H, d, J=8.3 Hz), 6.93 (1H, s), 6.81 (1H,d, J=8.1 Hz), 6.70-6.72 (3H, m), 3.81 (2H, t, J=6.4 Hz), 3.61 (2H,br.s), 2.78 (2H, t, J=6.4 Hz), 2.22 (3H, s).

[1164] Step 3. 2-[4-(2-Ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1165] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-Amino-5-methylanilino)phenyl]ethanol (step 2) and propionylchloride.

[1166]¹H-NMR (CDCl₃) δ 7.64 (1H, d, J=8.3 Hz), 7.42 (2H, d, J=8.0 Hz),7.28 (2H, d, J=8.0 Hz), 7.08 (1H, d, J=8.3 Hz), 6.87 (1H, s), 4.38 (2H,t, J=6.9 Hz), 3.06 (2H, t, J=6.9 Hz), 2.76 (2H, q, J=7.5 Hz), 2.41 (3H,s), 2.36 (2H, q, J=7.7 Hz), 1.35 (3H, t, J=7.5 Hz), 1.15 (3H, t, J=7.7Hz).

[1167] Step 4.2-[4-(2-Ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1168] The title compound was prepared according to the proceduredescribed in 6 of Example 1 from2-[4-(2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1169]¹H-NMR (CDCl₃) δ 7.64 (1H, d, J=8.1 Hz), 7.45 (2H, d, J=8.1 Hz),7.19-7.30 (2H, m), 7.08 (1H, d, J=8.1 Hz), 6.88 (1H, s), 3.99 (2H, t,J=6.6 Hz), 3.00 (2H, t, J=6.6 Hz), 2.77 (2H, q, J=7.6 Hz), 2.40 (3H, s),1.33 (3H, t, J=7.6 Hz).

[1170] Step 5.1-[4-(2-Chloroethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazole

[1171] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1172]¹H-NMR (CDCl₃) δ 7.65 (1H, d, J=8.2 Hz), 7.43 (2H, d, J=8.2 Hz),7.31 (2H, d, J=8.2 Hz), 7.07 (1H, d, J=8.2 Hz), 6.88 (1H, s), 3.82 (2H,t, J=7.0 Hz), 3.19 (2H, t, 7.0 Hz), 2.77 (2H, q, J=7.6 Hz), 2.41 (3H,s), 1.33 (3H, t, J=7.6 Hz).

[1173] Step 6. 2-[4-(2-Ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1174] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazole (step 5).

[1175]¹H-NMR (CDCl₃) δ 7.64 (1H, d, J=8.2 Hz), 7.43 (2H, d, J=8.2 Hz),7.31 (2H, d, J=8.2 Hz), 7.08 (1H, d, J=8.2 Hz), 6.87 (1H, s), 3.62 (2H,t, J=7.0 Hz), 3.01 (2H, t, J=7.0 Hz), 2.77 (2H, q, J=7.6 Hz), 2.37 (3H,s), 1.33 (3H, t, J=7.6 Hz).

[1176] Step 7.2-[4-(2-Ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1177] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 6).

[1178]¹H-NMR (CDCl₃) δ 7.64 (1H, d, J=8.3 Hz), 7.40 (2H, d, J=8.2 Hz),7.28 (2H, d, J=8.2 Hz), 7.07 (1H, d, J=8.3 Hz), 6.88 (1H, s), 3.07 (2H,br.s), 2.87 (2H, t, J=6.8 Hz), 2.76 (2H, q, J=7.6 Hz), 2.40 (3H, s),1.33 (3H, t, J=7.6 Hz).

[1179] Step 8.6-Methyl-2-Ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1180] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 7).

[1181]¹H-NMR (CDCl₃) δ 7.73 (2H, d, J=8.3 Hz), 7.66 (1H, d, J=8.0 Hz),7.27-7.38 (6H, m), 7.09 (1H, d, J=8.0 Hz), 6.88 (1H, s), 3.59-3.63 (2H,m), 2.95 (2H, t, J=6.6 Hz), 2.77 (2H, q, J=7.5 Hz), 2.41 (3H, s), 2.39(3H, s), 1.33 (3H, t, J=7.5 Hz).

Example 526-Methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1182] The title compound was prepared according to the proceduredescribed in Example 2 from6-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 51).

[1183] mp 151-165° C.; ¹H-NMR (DMSO-d₆) δ 7.64 (2H, d, J=8.0 Hz), 7.51(1H, d, J=8.2 Hz), 7.33-7.42 (4H, m), 7.15 (2H, d, J=8.0 Hz), 7.02 (1H,dd, J=1.4 Hz, 8.2 Hz), 6.87 (1H, s), 3.18 (2H, br.s), 2.65-2.78 (4H, m),2.34 (3H, s), 2.78 (3H, s), 1.21 (3H, t, J=7.6 Hz).

Example 537-Methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1184] Step 1. 2-[4-(2-Methyl-6-nitroanilino)phenyl]ethanol

[1185] The title compound was prepared according to the proceduredescribed in step 1 Example 45 from 6-methyl-2-nitroaniline and4-bromophenylethyl alcohol.

[1186]¹H-NMR (CDCl₃) δ 8.28 (1H, br.s), 7.96 (1H, d, J=8.4 Hz),7.39-7.44 (1H, m), 7.02-7.12 (3H, m), 6.72 (2H, d, J=8.4 Hz), 3.82 (2H,t, J=6.5 Hz), 2.81 (2H, t, J=6.5 Hz), 2.08 (3H, s).

[1187] Step 2. 2-[4-(2-Amino-6-methylanilino)phenyl]ethanol

[1188] The title compound was prepared according to the proceduredescribed in step 2 of Example 26 from2-[4-(2-methyl-6-nitroanilino)phenyl]ethanol (step 1).

[1189]¹H-NMR (CDCl₃) δ 6.97-7.03 (3H, m), 6.66 (2H, d, J=7.6 Hz), 6.52(2H, d, J=7.6 Hz), 4.97 (1H, br.s), 3.86 (2H, br.s), 3.79 (2H, t, J=6.4Hz), 2.76 (2H, t, J=6.4 Hz), 2.16 (3H, s).

[1190] Step 3. 2-[4-(2-Ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1191] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-6-methylanilino)phenyl]ethanol (step 2) and propionylchloride.

[1192] TLC Rf=0.6 (hexane:ethyl acetate=1:1).

[1193] Step 4.2-[4-(2-Ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1194] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1195]¹H-NMR (CDCl₃) δ 7.63 (1H, d, J=8.0 Hz), 7.38-7.41 (2H, m),7.26-7.31 (2H, m), 7.14 (1H, dd, J=7.4 Hz, 8.0 Hz), 6.91 (1H, d, J=7.4Hz), 3.98 (2H, t, J=6.6 Hz), 3.01 (2H, t, J=6.6 Hz), 2.63 (2H, q, J=7.5Hz), 1.89 (3H, s), 1.31 (3H, t, J=7.5 Hz).

[1196] Step 5.1-[4-(2-Chloroethyl)phenyl]-2-ethyl-7-methyl-1H-benzimidazole

[1197] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1198]¹H-NMR (CDCl₃) δ 7.64 (1H, d, J=8.1 Hz), 7.26-7.39 (4H, m), 7.14(1H, dd, J=7.4 Hz, 8.1 Hz), 6.91 (1H, d, J=7.4 Hz), 3.81 (2H, t, J=7.2Hz), 3.19 (2H, d, J=7.2 Hz), 2.63 (2H, q, J=7.6 Hz), 1.88 (3H, s), 1.32(3H, t, J=7.6 Hz).

[1199] Step 6. 2-[4-(2-Ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1200] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-7-methyl-1H-benzimidazole (step 5).

[1201]¹H-NMR (CDCl₃) δ 7.64 (1H, d, J=7.4 Hz), 7.39 (2H, d, J=8.0 Hz),7.31 (2H, d, J=8.0 Hz), 7.14 (1H, dd, J=7.4 Hz, 8.1 Hz), 6.91 (1H, d,J=8.1 Hz), 3.61 (2H, t, J=6.8 Hz), 3.02 (2H, t, J=6.8 Hz), 2.63 (2H, q,J=7.6 Hz), 1.89 (3H, s), 1.31 (3H, t, J=7.5 Hz).

[1202] Step 7.2-[4-(2-Ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1203] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 6).

[1204]¹H-NMR (CDCl₃) δ 7.64 (1H, d, J=7.9 Hz), 7.36 (2H, d, J=8.2 Hz),7.28 (2H, d, J=8.2 Hz), 7.14 (1H, dd, J=7.5 Hz, 7.9 Hz), 6.91 (1H, d,J=7.5 Hz), 3.06 (2H, t, J=6.8 Hz), 2.87 (2H, t, J=6.8 Hz), 2.63 (2H, q,J=7.5 Hz), 1.89 (3H, s), 1.32 (3H, t, J=7.5 Hz).

[1205] Step 8.2-Ethyl-7-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1206] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 7).

[1207] MS (ESI) m/z 477 (M+H)⁺, ¹H-NMR (CDCl₃) δ 7.75 (2H, d, J=8.3 Hz),7.62 (1H, d, J=7.9 Hz), 7.28-7.33 (5H, m), 7.14 (2H, d, J=7.6 Hz), 6.91(1H, d, J=7.9 Hz), 6.72 (1H, br.s), 3.58 (2H, d, J=6.8 Hz), 2.93 (2H, t,J=6.8 Hz), 2.62 (2H, q, J=7.6 Hz), 2.41 (3H, s), 1.86 (3H, s), 1.29 (3H,t, J=7.6 Hz).

Example 547-Methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1208] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-7-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 53).

[1209]¹H-NMR (DMSO-d₆) δ 7.63 (2H, d, J=7.4 Hz), 7.47 (1H, d, J=8.1 Hz),7.36 (4H, s), 7.15 (2H, d, J=7.7 Hz), 7.06 (1H, dd, J=7.2 Hz, 8.1 Hz),6.87 (1H, d, J=7.2 Hz), 5.99 (1H, br.s), 3.16 (2H, br.s), 2.76 (2H,br.s), 2.52 (2H, q, J=7.6 Hz), 2.28 (3H, s), 1.82 (3H, s), 1.19 (3H, t,J=7.6 Hz); IR (KBr) ν_(max) 3400, 1610, 1525, 1290, 1132, 1095, 820, 751cm⁻¹.

Example 554-Chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1210] Step 1. 2-[4-(3-Chloro-2-nitroanilino)phenyl]ethanol

[1211] A mixture of 2,6-dichloronitrobenzene (Norman, M. H.; Chen, N.;et al. PCT Int Appl., WO 9940091 (1999)., Spada, A. P.; Fink, C. A.;Myers, M. R. PCT Int. Appl., WO 9205177 (1992)., 6.3 g, 32.8 mmol),4-aminophenylethyl alcohol (4.9 g, 36 mmol) and sodium acetate (3.2 g,39.3 mmol) was placed in a sealed tube and heated at 160° C. for 3 h.After cooling, the mixture was poured into water (100 mL) and extractedwith ethyl acetate (300 mL). The organic layer was washed with 2Naqueous NaOH (100 mL) and brine (100 mL), then dried (Na₂SO₄), andconcentrated. Purification by flash column chromatography on silica geleluting with hexane/ethyl acetate (1:1) to afford 4.57 g (72%) of thetitle compound as a red oil: ¹H-NMR (CDCl₃) δ 7.09-7.28 (6H, m), 6.91(1H, dd, J=2.0, 7.1 Hz), 3.87 (2H, t, J=6.6 Hz), 2.86 (2H, t, J=6.6 Hz).

[1212] Step 2. 2-[4-(2-Amino-3-chloroanilino)phenyl]ethanol

[1213] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[4-(3-chloro-2-nitroanilino)phenyl]ethanol (step 1).

[1214]¹H-NMR (CDCl₃) δ 7.06-7.10 (3H, m), 7.00 (1H, dd, J=1.0 Hz, 7.9Hz), 6.62-6.73 (3H, m), 5.16 (1H, br.s), 4.14 (2H, br.s), 3.81 (2H, t,J=6.1 Hz), 2.77 (2H, t, J=6.1 Hz).

[1215] Step 3. 2-[4-(4-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1216] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-3-chloroanilino)phenyl]ethanol (step 2) and propionylchloride.

[1217] TLC Rf=0.5 (hexane:ethyl acetate=1:1).

[1218] Step 4.2-[4-(4-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1219] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(4-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1220]¹H-NMR (CDCl₃) δ 7.45 (2H, d, J=8.6 Hz), 7.26-7.31 (3H, m), 7.09(1H, d, J=7.9 Hz), 6.96 (1H, dd, J=0.9 Hz, 7.9 Hz), 3.99 (2H, t, J=6.6Hz), 3.00 (2H, t, J=6.6 Hz), 2.84 (2H, q, J=7.5 Hz), 1.30 (3H, t, J=7.5Hz).

[1221] Step 5.4-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole

[1222] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(4-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1223]¹H-NMR (CDCl₃) δ 7.45 (2H, d, J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz),7.27 (1H, s), 7.10 (1H, d, J=8.1 Hz), 6.98 (1H, d, J=8.1 Hz), 3.81 (2H,t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 2.84 (2H, q, J=7.6 Hz), 1.31 (3H,t, J=7.6 Hz).

[1224] Step 6. 2-[4-(4-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1225] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from4-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole (step 5).

[1226]¹H-NMR (CDCl₃) δ 7.45 (2H, d, J=8.2 Hz), 7.29-7.33 (3H, m), 7.10(1H, dd, J=8.1 Hz, 7.7 Hz), 6.96 (1H, d, J=7.7 Hz), 3.62 (2H, t, J=7.1Hz), 3.02 (2H, t, J=7.1 Hz), 2.84 (2H, q, J=7.6 Hz), 1.30 (3H, t, J=7.6Hz).

[1227] Step 7.2-[4-(4-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1228] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from2-[4-(4-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 6).

[1229]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.1 Hz), 7.29-7.33 (3H, m), 7.09(1H, dd, J=7.7 Hz, 7.9 Hz), 7.99 (1H, d, J=7.9 Hz), 3.07 (2H, t, J=6.8Hz), 2.87 (2H, t, J=6.8 Hz), 2.85 (2H, q, J=7.6 Hz), 1.30 (3H, t, J=7.6Hz).

[1230] Step 8.4-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1231] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(4-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 7).

[1232] MS (ESI) m/z 498 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.73 (2H, d, J=8.5 Hz),7.28-7.38 (7H, m), 7.09 (1H, d, J=7.9 Hz), 6.97 (1H, d, J=7.9 Hz), 6.69(1H, br.s), 3.58 (2H, t, J=6.9 Hz), 2.94 (2H, t, J=6.9 Hz), 2.83 (2H, q,J=7.5 Hz), 2.40 (3H, s), 1.31 (3H, t, J=7.5 Hz).

Example 564-Chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1233] The title compound was prepared according to the proceduredescribed in Example 2 from4-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 54).

[1234]¹H-NMR (DMSO-d₆) δ 7.62 (2H, d, J=8.0 Hz), 7.41 (4H, s), 7.29 (1H,d, J=6.6 Hz), 7.12-7.18 (3H, m), 7.02-7.04 (1H, m), 3.18 (2H, br.s),2.70-2.79 (4H, m), 2.27 (3H, s), 1.23 (3H, t, J=7.4 Hz); IR (KBr)ν_(max) 3385, 1602, 1519, 1433, 1174, 1130, 1085, 813 cm⁻¹.

Example 575-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1235] Step 1. 2-[4-(4-Chloro-2-nitroanilino)phenyl]ethanol

[1236] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,5-dichloronitrobenzene and4-aminophenylethyl alcohol.

[1237]¹H-NMR (CDCl₃) δ 9.42 (1H, s), 8.20 (1H, d, J=2.0 Hz), 7.35-7.10(6H, m), 3.96-3.85 (2H, m), 2.91 (2H, t, J=7.0 Hz).

[1238] Step 2. 2-[4-(2-Amino-4-chloroanilino)phenyl]ethanol

[1239] The title compound was prepared according to the proceduredescribed in step 3 of Example 6 from2-[4-(4-chloro-2-nitroanilino)phenyl]ethanol (step 1).

[1240]¹H-NMR (CDCl₃) δ 7.30-7.05 (4H, m), 6.83-6.62 (3H, m), 5.15 (1H,br.s), 3.86-3.75 (2H, m), 3.75 (2H, br.s), 2.77 (2H, t, J=7.0 Hz).

[1241] Step 3. 2-[4-(5-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1242] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-4-chloroanilino)phenyl]ethanol (step 2) and propionylchloride.

[1243]¹H-NMR (CDCl₃) δ 7.75 (1H, d, J=2.0 Hz), 7.43 (2H, d, J=8.0 Hz),7.28 (2H, d, J=8.0 Hz), 7.15 (1H, dd, J=2.0, 8.6 Hz), 6.99 (1H, d, J=8.6Hz), 4.38 (2H, t, J=7.0 Hz), 3.07 (2H, t, J=7.0 Hz), 2.78 (2H, q, J=7.5Hz), 2.36 (2H, q, J=7.5 Hz), 1.24 (3H, t, J=7.5 Hz), 1.15 (3H, t, J=7.5Hz).

[1244] Step 4.2-[4-(5-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1245] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1246]¹H-NMR (CDCl₃) δ 7.75 (1H, d, J=2.0 Hz), 7.46 (2H, d, J=8.4 Hz),7.29 (2H, d, J=8.4 Hz), 7.15 (1H, dd, J=2.0, 8.6 Hz), 7.00 (1H, d, J=8.6Hz), 3.99 (2H, t, J=6.5 Hz), 3.00 (2H, t, J=6.5 Hz), 2.78 (2H, q, J=7.5Hz), 1.26 (3H, t, J=7.5 Hz).

[1247] Step 5. 2-[4-(5-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1248] The title compound was prepared according to the proceduredescribed in step 5 Example 26 from2-[4-(5-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1249] MS (EI) m/z 325 (M⁺); ¹H-NMR (CDCl₃) δ 7.75 (1H, d, J=2.0 Hz),7.45 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 7.15 (1H, dd, J=2.0, 8.6Hz), 6.99 (1H, d, J=8.6 Hz), 3.62 (2H, t, J=7.0 Hz), 3.02 (2H, t, J=7.0Hz), 2.78 (2H, q, J=7.5 Hz), 1.26 (3H, t, J=7.5 Hz).

[1250] Step 6.2-[4-(5-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1251] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from2-[4-(5-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 5).

[1252]¹H-NMR (CDCl₃) δ 7.75 (1H, d, J=2.0 Hz), 7.41 (2H, d, J=8.3 Hz),7.27 (2H, d, J=8.3 Hz), 7.14 (1H, dd, J=2.0, 8.6 Hz), 6.99 (1H, d, J=8.6Hz), 3.08 (2H, t, J=7.0 Hz), 2.86 (2H, t, J=7.0 Hz), 2.77 (2H, q, J=7.5Hz), 1.34 (3H, t, J=7.5 Hz).

[1253] Step 7.5-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1254] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(5-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 6).

[1255]¹H-NMR (CDCl₃) δ 7.76 (1H, d, J=1.8 Hz), 7.72 (2H, d, J=8.4 Hz),7.39 (2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.3 Hz),7.17 (1H, dd, J=8.6, 1.8 Hz), 7.00 (1H, d, J=8.6 Hz), 6.73 (1H, br.s),3.59-3.53 (2H, m), 2.94 (2H, t, J=7.0 Hz), 2.81 (2H, q, J=7.5 Hz), 1.34(3H, t, J=7.5 Hz).

Example 58 2-[4-(5-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[1256] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(5-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 ofExample 57).

[1257]¹H-NMR (CDCl₃) δ 7.92 (2H, d, J=8.4 Hz), 7.74 (1H, d, J=2.0 Hz),7.34 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz),7.16 (1H, dd, J=8.5, 2.0 Hz), 6.99 (1H, d, J=8.5 Hz), 4.74 (1H, br.s),4.37 (2H, t, J=6.8 Hz), 3.01 (2H, t, J=6.8 Hz), 2.75 (2H, q, J=7.6 Hz),1.33 (3H, t, J=7.6 Hz).

Example 596-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1258] Step 1. 2-[(5-Chloro-2-nitroanilino)phenyl]ethanol

[1259] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,4-dichloronitrobenzene and4-aminophenylethyl alcohol.

[1260]¹H-NMR (CDCl₃) δ 9.52 (1H, br.s), 8.16 (1H, d, J=9.2H), 7.33 (2H,d, J=8.2 Hz), 7.25 (2H, d, J=8.2 Hz), 7.13 (1H, d, J=2.2 Hz), 6.71 (1H,dd, J=9.2, 2.2 Hz), 3.92 (q, 2H, J=6.4 Hz), 2.92 (t, 2H, J=6.4 Hz).

[1261] Step 2. 2-[(2-Amino-5-chloroanilino)phenyl]ethanol

[1262] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[(5-chloro-2-nitroanilino)phenyl]ethanol (step 1).

[1263]¹H-NMR (CDCl₃) δ 7.12-7.09 (3H, m), 6.92 (1H, dd, J=8.4, 2.4 Hz),6.78-6.70 (3H, m), 5.16 (1H, br.s), 3.83 (2H, t, J=6,6 Hz), 2.81 (2H, t,J=6.6 Hz).

[1264] Step 3. 2-[4-(6-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1265] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[(2-amino-5-chloroanilino)phenyl]ethanol (step 2) and propionylchloride.

[1266]¹H-NMR (CDCl₃) δ 7.67 (1H, d, J=8.6 Hz), 7.44 (2H, d, J=8.4 Hz),7.28 (2H, d, J=8.4 Hz), 7.22 (1H, dd, J=8.4, 2.0 Hz), 7.07 (1H, d, J=2.0Hz), 4.38 (2H, t, J=7.0 Hz), 3.07 (2H, t, J=7.0 Hz), 2.77 (2H, q, J=7.5Hz), 2.36 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.5 Hz), 1.15 (3H, t, J=7.5Hz).

[1267] Step 4.2-[4-(6-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1268] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(6-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1269]¹H-NMR (CDCl₃) δ 7.67 (1H, d, J=8.6 Hz), 7.46 (2H, d, J=8.6 Hz),7.30-7.26 (3H, m), 7.22 (1H, dd, J=8.6, 2.2 Hz), 7.08 (1H, d, J=2.0 Hz),3.99 (2H, q, J=6.4 Hz), 3.01 (2H, t, J=6.4 Hz), 2.78 (2H, q, J=7.6 Hz),1.72 (1H, t, J=5.6 Hz), 1.35 (3H, t, J=7.6 Hz).

[1270] Step 5. 2-[4-(6-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1271] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-[4-(6-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1272] MS (EI) m/z 325 (M⁺).

[1273] Step 6.2[4-(6-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1274] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(6-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 5).

[1275]¹H-NMR (CDCl₃) δ 7.67 (1H, d, J=8.6 Hz), 7.41 (2H, d, J=8.4 Hz),7.31-7.19 (3H, m), 7.12 (1H, d, J=2.0 Hz), 4.66 (2H, br.s), 3.23-3.17(2H, m), 3.08-3.04 (2H, m), 2.75 (2H, q, J=7.5 Hz), 1.33 (3H, t, J=7.5Hz).

[1276] Step 7.6-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1277] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(6-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 6).

[1278]¹H-NMR (CDCl₃) δ 7.74 (2H, d, J=8.4 Hz), 7.67 (1H, d, J=8.4 Hz),7.37 (2H, d, J=8.4 Hz), 7.30-7.20 (6H, m), 7.05 (1H, d, J=2.0 Hz), 6.73(1H, m), 3.62-3.55 (2H, m), 2.93 (2H, t, J=7.2 Hz), 2.77 (2H, t, J=7.5Hz), 1.32 (3H, t, J=7.5 Hz).

Example 606-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1279] The title compound was prepared according to the proceduredescribed in Example 2 from6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 59).

[1280]¹H-NMR (DMSO-d₆) δ 7.64 (1H, d, J=8.6 Hz), 7.59 (2H, d, J=8.1 Hz),7.38 (4H, m), 7.22 (1H, dd, J=8.6, 2.0 Hz), 7.11 (2H, d, J=8.1 Hz), 7.05(1H, d, J=2.0 Hz), 3.15 (2H, m), 2.74-2.66 (4H, m), 2.25 (3H, s), 1.21(3H, t, J=7.4 Hz); IR (KBr) ν_(max) 1601, 1516, 1398, 1178, 1130, 1084cm⁻¹.

Example 614-(6-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamate

[1281] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(6-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 ofExample 59).

[1282] mp-183-187° C.; ¹H-NMR (DMSO-d₆) δ 7.75 (2H, d, J=8.1 Hz), 7.66(1H, d, J=8.6 Hz), 7.43 (4H, s), 7.40 (2H, d, J=8.1 Hz), 7.24 (1H, dd,J=8.6, 2.0 Hz), 7.03 (1H, d, J=2.0 Hz), 4.27 (2H, t, J=6.6 Hz), 2.95(2H, t, J=6.6 Hz), 2.70 (2H, q, J=7.5 Hz), 2.34 (3H, s), 1.22 (3H, t,J=7.5 Hz); IR (KBr) ν_(max) 1744, 1516, 1352, 1225, 1165 cm⁻¹.

Example 622-Butyl-6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]butyl}phenyl)-1H-benzimidazole

[1283] Step 1. 2-[4-(2-Butyl-6-chloro-1H-benzimidazol-1-yl)phenyl]ethylpentanoate

[1284] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[(2-amino-5-chloroanilino)phenyl]ethanol (step 2 of Example 59) andpentanoyl chloride.

[1285]¹H-NMR (CDCl₃) δ 7.66 (1H, d, J=8.4 Hz), 7.44 (2H, d, J=8.1 Hz),7.28 (2H, d, J=8.1 Hz), 7.22 (1H, dd, J=8.4, 2.0 Hz), 7.06 (1H, d, J=2.0Hz), 4.38 (2H, t, J=6.8 Hz), 3.07 (2H, t, J=6.8 Hz), 2.74 (2H, t, J=7.7Hz), 2.33 (2H, t, J=7.5 Hz), 1.81-1.70 (2H, m), 1.66-1.56 (2H, m),1.40-1.28 (4H, m), 0.94-0.84 (6H, m).

[1286] Step 2.2-[4-(2-Butyl-6-chloro-1H-benzimidazol-1-yl)phenyl]ethanol

[1287] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-butyl-6-chloro-1H-benzimidazol-1-yl)phenyl]ethyl pentanoate(step 1).

[1288]¹H-NMR (CDCl₃) δ 7.66 (1H, d, J=8.6 Hz), 7.46 (2H, d, J=8.1 Hz),7.29-7.26 (2H, m), 7.22 (1H, dd, J=8.6, 2.0 Hz), 7.07 (1H, d, J=2.0 Hz),4.00 (2H, q, J=6.4 Hz), 3.01 (2H, t, J=6.4 Hz), 2.75 (2H, t, J=7.5 Hz),2.24-2.19 (1H, m), 1.81-1.71 (2H, m), 1.37-1.26 (2H, m), 0.87 (3H, t,J=7.3 Hz).

[1289] Step 3. 2-[4-(2-Butyl-6-chloro-1H-benzimidazol-1-yl)phenyl]ethylazide

[1290] The title compound was prepared according to the proceduredescribed in step 4 of Example from2-[4-(2-butyl-6-chloro-1H-benzimidazol-1-yl)phenyl]ethanol (step 2).

[1291]¹H-NMR (CDCl₃) δ 7.66 (1H, d, J=8.6 Hz), 7.45 (2H, d, J=8.3 Hz),7.29 (2H, d, J=8.3 Hz), 7.22 (1H, dd, J=8.6, 2.0 Hz), 7.07 (1H, d, J=2.0Hz), 3.62 (2H, t, J=7.0 Hz), 3.02 (2H, t, J=7.0 Hz), 2.74 (2H, t, J=7.5Hz), 1.80-1.70 (2H, m), 1.40-1.26 (2H, m), 0.86 (2H, t, J=7.3 Hz).

[1292] Step 3.2-[4-(2-Butyl-6-chloro-1H-benzimidazol-1-yl)phenyl]ethylamine

[1293] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-butyl-6-chloro-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 2).

[1294]¹H-NMR (CDCl₃) δ 7.66 (1H, d, J=8.6 Hz), 7.43 (2H, d, J=8.2 Hz),7.27 (2H, d, J=8.2 Hz), 7.21 (1H, dd, J=8.6, 2.0 Hz), 7.08 (1H, d, J=2.0Hz), 3.11 (2H, t, J=7.1 Hz), 2.91 (2H, t, J=7.1 Hz), 2.74 (2H, t, J=7.4Hz), 1.81-1.70 (2H, m), 1.41-1.27 (2H, m), 0.86 (3H, t, J=7.4 Hz).

[1295] Step 4.2-Butyl-6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1296] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-butyl-6-chloro-1H-benzimidazol-1-yl)phenyl]ethylamine (step 3).

[1297]¹H-NMR (CDCl₃) δ 7.75 (2H, d, J=8.4 Hz), 7.66 (1H, d, J=8.2 Hz),7.38 (2H, d, J=8.4 Hz), 7.30-7.20 (6H, m), 7.05 (1H, d, J=2.0 Hz),6.77-6.72 (1H, m), 3.61-3.55 (2H, m), 2.96-2.92 (2H, m), 2.74 (2H, t,J=7.5 Hz), 2.39 (3H, s), 1.78-1.67 (2H, m), 1.35-1.26 (2H, m), 0.84 (3H,t, J=7.3 Hz).

Example 632-Butyl-6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]butyl}phenyl)-1H-benzimidazole,sodium salt

[1298] The title compound was prepared according to the proceduredescribed in Example 2 from2-butyl-6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 62).

[1299] mp 137-145° C.; ¹H-NMR (DMSO-d₆) δ 7.65-7.63 (1H, m), 7.59 (2H,d, J=7.8 Hz), 7.38 (4H, s), 7.23-7.20 (1H, m), 7.12 (2H, d, J=7.8 Hz),7.04 (1H, s), 3.15 (2H, m), 2.72-2.67 (4H, m), 2.26 (3H, s), 1.66-1.61(2H, m), 1.29-1.22 (2H, m), 0.79 (3H, t, J=7.5 Hz); IR (KBr) ν_(max)1603, 1520, 1458, 1396, 1130, 1086 cm⁻¹.

Example 647-Chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1300] Step 1. 2-[4-(2-Chloro-6-nitroanilino)phenyl]ethanol

[1301] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,3-dichloronitrobenzene and4-aminophenylethyl alcohol.

[1302]¹H-NMR (CDCl₃) δ 8.11 (1H, br.s), 8.00 (1H, dd, J=1.5 Hz, 8.5 Hz),7.61 (1H, dd, J=1.5 Hz, 7.9 Hz), 7.12 (2H, d, J=8.4 Hz), 7.03 (1H, dd,J=7.9 Hz, 8.5 Hz), 6.80 (2H, d, J=8.4 Hz), 3.82 (2H, t, J=6.6 Hz), 2.81(2H, d, J=6.6 Hz).

[1303] Step 2. 2-[4-(2-Amino-6-chloroanilino)phenyl]ethanol

[1304] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[4-(2-cloro-6-nitroanilino)phenyl]ethanol (step 1).

[1305]¹H-NMR (CDCl₃) δ 7.04 (2H, d, J=7.8 Hz), 6.97 (1H, dd, J=7.9 Hz,8.0 Hz), 6.82 (1H, dd, J=1.5 Hz, 7.9 Hz), 6.66 (1H, dd, J=1.5 Hz, 8.0Hz), 6.59 (2H, d, J=7.8 Hz), 5.36 (1H, br.s), 3.94 (2H, br.s), 3.78 (2H,t, J=6.6 Hz), 2.75 (2H, d, J=6.6 Hz).

[1306] Step 3. 2-[4-(7-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1307] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-6-chloroanilino)phenyl]ethanol (step 2) and propionylchloride.

[1308] TLC Rf=0.6 (hexane:ethyl acetate=1:1).

[1309] Step 4.2-[4-(7-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1310] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-amino-6-chloroanilino)phenyl]ethyl propionate (step 3).

[1311]¹H-NMR (CDCl₃) δ 7.68 (1H, dd, J=1.9 Hz, 7.0 Hz), 7.39 (2H, d,J=8.2 Hz), 7.28 (2H, d, J=8.2 Hz), 7.11-7.20 (2H, m), 3.97 (2H, t, J=6.6Hz), 3.01 (2H, t, J=6.6 Hz), 2.65 (2H, q, J=7.6 Hz), 1.32 (3H, t, J=7.6Hz).

[1312] Step 5.7-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole

[1313] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(7-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1314]¹H-NMR (CDCl₃) δ 7.69 (1H, dd, J=2.2 Hz, 7.1 Hz), 7.37 (2H, d,J=8.2 Hz), 7.31 (2H, d, J=8.2 Hz), 7.11-7.17 (2H, m), 3.81 (2H, t, J=7.3Hz), 3.19 (2H, t, J=7.3 Hz), 2.65 (2H, q, J=7.5 Hz), 1.33 (3H, t, J=7.5Hz).

[1315] Step 6. 2-[4-(7-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1316] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from7-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole (step 5).

[1317]¹H-NMR (CDCl₃) δ 7.69 (1H, dd, J=1.8 Hz, 7.4 Hz), 7.38 (2H, d,J=8.2 Hz), 7.34 (2H, d, J=8.2 Hz), 7.11-7.28 (2H, m), 3.60 (2H, t, J=7.0Hz), 3.02 (2H, t, J=7.0 Hz), 2.64 (2H, q, J=7.6 Hz), 1.32 (3H, t, J=7.6Hz).

[1318] Step 7.2-[4-(7-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1319] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from2-[4-(7-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 6).

[1320]¹H-NMR (CDCl₃) δ 7.69 (1H, d, J=7.9 Hz), 7.35 (2H, d, J=8.3 Hz),7.28 (2H, d, J=8.3 Hz), 7.11-7.19 (2H, m), 3.06 (2H, t, J=6.8 Hz), 2.88(2H, t, J=6.8 Hz), 2.65 (2H, q, J=7.5 Hz), 1.33 (3H, t, J=7.5 Hz).

[1321] Step 8.7-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1322] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(7-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 7).

[1323] MS (ESI) m/z 498 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.74 (2H, d, J=8.4 Hz),7.69 (1H, dd, J=1.9 Hz, 7.4 Hz), 7.29-7.32 (6H, m), 7.11-7.20 (2H, m),6.72 (1H, br.s), 3.59 (2H, t, J=6.9 Hz), 2.93 (2H, t, J=6.9 Hz), 2.64(2H, q, J=7.6 Hz), 2.42 (3H, s), 1.31 (3H, t, J=7.6 Hz).

Example 657-Chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1324] The title compound was prepared according to the proceduredescribed in Example 2 from7-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 64).

[1325]¹H-NMR (DMSO-dr) δ 7.62-7.64 (3H, m), 7.31-7.39 (4H, m), 7.14-7.20(4H, m), 6.00 (1H, br.s), 3.17 (2H, br.s), 2.75 (2H, br.s), 2.55 (2H, q,J=7.8 Hz), 2.29 (3H, s), 1.21 (3H, t, J=7.8 Hz); IR (KBr) ν_(max) 3380,2891, 1605, 1520, 1425, 1285, 1126, 1075, 798 cm⁻¹.

Example 665-Fluoro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1326] Step 1. 2-[4-(4-Fluoro-2-nitroanilino)phenyl]ethanol

[1327] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,5-difluoronitrobenzene and4-aminophenylethyl alcohol.

[1328]¹H-NMR (CDCl₃) δ 9.32 (1H, s), 7.88-7.93 (1H, m), 7.11-7.30 (5H,m), 3.90 (2H, t, J=6.2 Hz), 2.90 (2H, t, J=6.2 Hz).

[1329] Step 2. 2-[4-(2-Amino-4-fluoroanilino)phenyl]ethanol

[1330] The title compound was prepared according to the proceduredescribed in step 2 of Example 26 from2-[4-(4-fluoro-2-nitroanilino)phenyl]ethanol (step 1).

[1331]¹H-NMR (CDCl₃) δ 6.98-7.06 (3H, m), 6.60 (2H, d, J=8.2 Hz), 6.49(1H, dd, J=2.8 Hz, 12.8 Hz), 6.41 (1H, dd, J=2.8 Hz, 8.4 Hz), 4.99 (1H,br.s), 3.94 (2H, br.s), 3.79 (2H, br.s), 2.76 (2H, t, J=6.4 Hz).

[1332] Step 3. 2-[4-(2-Ethyl-5-fluoro-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1333] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-4-fluoroanilino)phenyl]ethanol (step 2) and propionylchloride.

[1334] MS (EI) m/z 340 (M⁺).

[1335] Step 4.2-[4-(2-Ethyl-5-fluoro-1H-benzimidazol-1-yl)phenyl]ethanol

[1336] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-amino-4-fluoroanilino)phenyl]ethyl propionate (step 3).

[1337]¹H-NMR (CDCl₃) δ 7.40-7.47 (3H, m), 7.28 (2H, d, J=8.0 Hz),6.88-7.02 (2H, m), 3.98 (2H, t, J=6.3 Hz), 3.01 (2H, t, J=6.3 Hz), 2.78(2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz).

[1338] Step 5.1-[4-(2-Chloroethyl)phenyl]-2-ethyl-5-fluoro-1H-benzimidazole

[1339] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1340]¹H-NMR (CDCl₃) δ 7.42-7.46 (3H, m), 7.31 (2H, d, J=8.1 Hz),6.89-7.02 (2H, m), 3.81 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 2.78(2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.6 Hz).

[1341] Step 6. 2-[4-(2-Ethyl-5-fluoro-1H-benzimidazol-1-yl)phenyl]ethylazide

[1342] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-fluoro-1H-benzimidazole (step 5).

[1343]¹H-NMR (CDCl₃) δ 7.43-7.45 (3H, m), 7.31 (2H, d, J=8.2 Hz),6.89-7.02 (2H, m), 3.62 (2H, t, J=7.0 Hz), 3.01 (2H, t, J=7.0 Hz), 2.77(2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz).

[1344] Step 7.2-[4-(2-Ethyl-5-fluoro-1H-benzimidazol-1-yl)phenyl]ethylamine

[1345] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 6).

[1346]¹H-NMR (CDCl₃) δ 7.40-7.46 (3H, m), 7.27-7.29 (2H, m), 6.87-6.99(2H, m), 3.06 (2H, t, J=7.1 Hz), 2.87 (2H, t, J=7.1 Hz), 2.78 (2H, q,J=7.5 Hz), 1.35 (3H, t, J=7.5 Hz).

[1347] Step 8.5-Fluoro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1348] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl)phenyl]ethylamine (step 7).

[1349] MS (ESI) m/z 481 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.73 (2H, d, J=8.2 Hz),7.35-7.45 (3H, m), 7.24-7.29 (4H, m), 6.87-7.00 (2H, m), 6.73 (1H,br.s), 3.57 (2H, t, J=7.0 Hz), 2.93 (2H, t, J=7.0 Hz), 2.77 (2H, q,J=7.6 Hz), 2.39 (3H, s), 1.31 (3H, t, J=7.6 Hz).

Example 675-Fluoro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1350] The title compound was prepared according to the proceduredescribed in Example 2 from5-fluoro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 66).

[1351] mp 135-146° C.; MS (ESI) m/z 481 (M+H)⁺; ¹H-NMR (DMSO-d₆) δ 7.62(2H, d, J=8.1 Hz), 7.39-7.48 (5H, m), 6.97-7.15 (4H, m), 5.92 (1H,br.s), 2.67-2.76 (4H, m), 2.51 (2H, br.s), 2.27 (3H, s), 1.23 (3H, t,J=7.6 Hz).

Example 682-Butyl-6-fluoro-1-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-1H-benzimidazole

[1352] Step 1. 2-[4-(5-Fluoro-2-nitroanilino)phenyl]ethanol

[1353] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,4-difluoronitrobenzene and4-aminophenylethyl alcohol.

[1354]¹H-NMR (CDCl₃) δ 9.61 (1H, br.s), 8.26 (1H, dd, J=6.1, 9.5 Hz),7.32 (2H, d, J=8.2 Hz), 7.22 (2H, d, J=8.3 Hz), 6.78 (1H, dd, J=2.6,11.3 Hz), 6.47 (1H, ddd, J=2.2, 7.2, 9.7 Hz), 3.91 (2H, dt, J=6.2, 6.2Hz), 2.91 (2H, t, J=6.4 Hz), 1.52 (1H, t, J=5.7 Hz).

[1355] Step 2. 2-[4-(2-Amino-5-fluoroanilino)phenyl]ethanol

[1356] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[4-(5-fluoro-2-nitroanilino)phenyl]ethanol (step 1).

[1357]¹H-NMR (CDCl₃) δ 7.12 (2H, d, J=8.4 Hz), 6.87 (1H, dd, J=2.7, 10.1Hz), 6.83 (2H, d, J=8.4 Hz), 6.72 (1H, dd, J=5.7, 8.6 Hz), 6.63 (1H,ddd, J=2.7, 8.4, 8.4 Hz), 5.30 (1H, s), 3.83 (2H, t, J=6.4 Hz), 2.80(2H, t, J=6.4 Hz).

[1358] Step 3. 2-[4-(2-butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethylpentanoate

[1359] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-5-fluoroanilino)phenyl]ethanol (step 2) and pentanoylchloride.

[1360]¹H-NMR (CDCl₃) δ 7.67 (1H, dd, J=4.8, 8.8 Hz), 7.44 (2H, d, J=8.3Hz), 7.28 (2H, d, J=8.1 Hz), 7.04-6.95 (1H, m), 6.76 (1H, dd, J=2.6, 8.8Hz), 4.38 (2H, t, J=6.8 Hz), 3.07 (2H, t, J=6.8 Hz), 2.74 (2H, t, J=7.5Hz), 2.33 (2H, t, J=7.7 Hz), 1.81-1.55 (4H, m), 1.42-1.25 (4H, m), 6.91(3H, t, J=7.3 Hz), 0.87 (3H, t, J=7.3 Hz).

[1361] Step 4.2-[4-(2-butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethanol

[1362] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethyl pentanoate(step 3).

[1363]¹H-NMR (CDCl₃) δ 7.67 (1H, dd, J=4.8, 8.8 Hz), 7.46 (2H, d, J=8.2Hz), 7.28 (2H, d, J=8.3 Hz), 6.99 (1H, ddd, J=2.4, 9.0, 9.5 Hz),4.10-3.85 (2H, m), 3.01 (2H, t, J=6.4 Hz), 2.74 (2H, t, J=7.7 Hz),1.84-1.69 (2H, m), 1.41-1.27 (2H, m), 0.87 (3H, t, J=7.3 Hz).

[1364] Step 5. 2-[4-(2-Butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethylazide

[1365] The title compound was prepared according to the proceduredescribed in step 5 Example 26 from2-[4-(2-butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1366] MS (EI) m/z 337 (M⁺); ¹H-NMR (CDCl₃) δ 7.68 (1H, dd, J=4.8, 8.8Hz), 7.45 (2H, d, J=8.1 Hz), 7.30 (2H, d, J=8.1 Hz), 7.04-6.94 (1H, m),6.77 (1H, dd, J=2.4, 8.6 Hz), 3.62 (2H, t, J=7.0 Hz), 3.02 (2H, t, J=6.8Hz), 2.74 (2H, t, J=7.7 Hz), 1.86-1.69 (2H, m), 1.41-1.2 (2H, m), 0.86(3H, t, J=7.3 Hz).

[1367] Step 6.2-[4-(2-Butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethylamine

[1368] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from2-[4-(2-butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 5).

[1369]¹H-NMR (CDCl₃) δ 7.67 (1H, dd, J=4.8, 8.8 Hz), 7.42 (2H, d, J=8.1Hz), 7.27 (2H, d, J=8.2 Hz), 7.05-6.95 (1H, m), 6.78 (1H, dd, J=2.6, 8.6Hz), 3.08 (2H, t, J=7.1 Hz), 2.88 (2H, t, J=6.8 Hz), 2.75 (2H, t, J=7.5Hz), 1.82-1.69 (2H, m), 1.41-1.24 (2H, m), 0.87 (3H, t, J=7.3 Hz).

[1370] Step 7.2-Butyl-6-fluoro-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1371] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethylamine (step 6).

[1372]¹H-NMR (CDCl₃) δ 7.73 (2H, d, J=8.4 Hz), 7.68 (1H, dd, J=4.6, 8.8Hz), 7.38 (2H, d, J=8.4 Hz), 7.32-7.24 (4H, m), 7.00 (1H, ddd, J=2.4,8.8, 11.2 Hz), 6.75 (1H, dd, J=2.4, 8.6 Hz), 3.64-3.54 (2H, m), 2.94(2H, t, J=7.0 Hz), 2.74 (2H, d, J=7.5 Hz), 1.80-1.65 (2H, m), 1.40-1.20(2H, m), 0.84 (3H, t, J=7.3 Hz).

Example 692-Butyl-6-fluoro-1-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-1H-benzimidazole,sodium salt

[1373] The title compound was prepared according to the proceduredescribed in Example 2 from2-butyl-6-fluoro-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole(Example 69).

[1374]¹H-NMR (DMSO-d₆) δ 7.70-7.57 (3H, m), 7.39 (4H, br), 7.14 (2H, d,J=8.0 Hz), 7.11-7.02 (1H, m), 8.85 (1H, dd, j=2.4, 9.2 Hz), 3.48-3.34(2H, m), 3.17 (2H, br), 2.80-2.65 (4H, m), 2.28 (3H, s), 1.72-1.55 (2H,m), 1.35-1.20 (2H, m), 0.80 (3H, t, J=7.1 Hz); IR (KBr) ν_(max) 3387,2872, 1601, 1516, 1479, 1400, 1130, 1086 cm⁻¹.

Example 702-Ethyl-6-fluoro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1375] Step 1. 2-[4-(6-Fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1376] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-5-fluoroanilino)phenyl]ethanol (step 2 of Example 68) andpropionyl chloride.

[1377] MS (EI) m/z 340 (M⁺); ¹H-NMR (CDCl₃) δ 7.67 (1H, dd, J=4.8, 8.8Hz), 7.43 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 6.99 (1H, ddd,J=2.5, 8.8, 9.5 Hz), 6.77 (1H, dd, J=2.5, 8.8 Hz), 4.38 (2H, t, J=6.6Hz), 3.07 (2H, t, J=6.6 Hz), 2.79 (2H, q, J=7.4 Hz), 2.35 (2H, q, J=7.4Hz), 1.35 (3H, t, J=7.4 Hz), 1.14 (3H, t, J=7.4 Hz).

[1378] Step 2.2-[4-(6-fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1379] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(6-fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 1).

[1380]¹H-NMR (CDCl₃) δ 7.67 (1H, dd, J=4.8, 8.8 Hz), 7.45 (2H, d, J=8.4Hz), 7.29 (2H, d, J=8.4 Hz), 6.99 (1H, ddd, J=2.5, 8.8, 9.5 Hz), 6.78(1H, dd, J=2.5, 8.8 Hz), 3.99 (2H, t, J=6.6 Hz), 3.00 (2H, t, J=6.6 Hz),2.77 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.5 Hz).

[1381] Step 3.6-fluoro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole

[1382] The title compound was prepared according to the proceduredescribed in step 7 Example 1 from2-[4-(6-fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 2).

[1383] MS (EI) m/z 302 (M⁺).

[1384] Step 4. 2-[4-(6-Fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1385] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from6-fluoro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole (step 3).

[1386] MS (EI) m/z 309 (M⁺); ¹H-NMR (CDCl₃) δ 7.68 (1H, dd, J=4.8, 8.8Hz), 7.44 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 6.99 (1H, ddd,J=2.5, 8.8, 9.6 Hz), 6.77 (1H, dd, J=2.5, 8.8 Hz), 3.62 (2H, t, J=6.9Hz), 3.02 (2H, t, J=6.9 Hz), 2.77 (2H, q, J=7.4 Hz), 1.34 (3H, t, J=7.4Hz).

[1387] Step 5.2-[4-(6-Fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1388] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from2-[4-(6-fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 4).

[1389]¹H-NMR (CDCl₃) δ 7.68 (1H, dd, J=4.8, 8.8 Hz), 7.43 (2H, d, J=8.2Hz), 7.28 (2H, d, J=8.2 Hz), 6.98 (1H, ddd, J=2.4, 8.8, 8.8 Hz), 6.82(1H, dd, J=2.4, 8.8 Hz), 3.37 (2H, br.s), 3.18 (2H, t, J=7.1 Hz), 3.01(2H, t, J=7.1 Hz), 2.76 (2H, q, J=7.5 Hz), 1.33 (3H, t, J=7.5 Hz).

[1390] Step 6.2-Ethyl-6-fluoro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1391] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(6-fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 5).

[1392]¹H-NMR (CDCl₃) δ 7.73 (2H, d, J=8.4 Hz), 7.68 (1H, dd, J=8.7, 4.9Hz), 7.37 (2H, d, J=8.4 Hz), 7.32-7.23 (4H, m), 7.00 (1H, ddd, J=9.5,8.7, 2.5 Hz), 6.79-6.69 (2H, m), 3.63-3.53 (2H, m), 2.94 (2H, t, J=7.5Hz), 2.76 (2H, q, J=7.5 Hz), 2.40 (3H, s), 1.32 (3H, t, J=7.5 Hz).

Example 715-Methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1393] Step 1. 2-[4-(4-Methoxy-2-nitroanilino)phenyl]ethanol

[1394] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2-chloro-5-methoxynitrobenzene and4-aminophenylethyl alcohol.

[1395]¹H-NMR (CDCl₃) δ 9.33 (1H, br.s), 7.63 (1H, d, J=3.0 Hz),7.17-7.27 (5H, m), 7.04-7.08 (1H, m), 3.88 (2H, br.s), 3.82 (3H, s),2.88 (2H, t, J=6.6 Hz).

[1396] Step 2. 2-[4-(2-Amino-4-methoxyanilino)amino]ethanol

[1397] The title compound was prepared according to the proceduredescribed in step 2 of Example 26 from2-[4-(4-methoxy-2-nitroanilino)phenyl]ethanol (step 1).

[1398]¹H-NMR (CDCl₃) δ 7.03 (2H, d, J=8.6 Hz), 6.98 (1H, d, J=8.4 Hz),6.59 (2H, d, J=8.6 Hz), 6.28-6.36 (2H, m), 3.77-3.85 (5H, m), 2.76 (2H,t, J=6.6 Hz).

[1399] Step 3. 2-[4-(2-Ethyl-5-methoxy-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1400] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-4-methoxyanilino)phenyl]ethanol (step 2).

[1401]¹H-NMR (CDCl₃) δ 7.40 (2H, d, J=8.0 Hz), 7.12-7.29 (3H, m), 6.97(1H, d, J=8.8 Hz), 6.82 (1H, dd, J=2.4 Hz, 8.8 Hz), 4.37 (2H, t, J=6.7Hz), 3.86 (3H, s), 3.05 (2H, t, J=6.7 Hz), 2.77 (2H, q, J=7.5 Hz), 2.36(2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz), 1.14 (3H, t, J=7.5 Hz).

[1402] Step 42-[4-(2-Ethyl-5-methoxy-1H-benzimidazol-1-yl)phenyl]ethanol

[1403] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-5-methoxy-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1404]¹H-NMR (CDCl₃) δ 7.43 (2H, d, J=8.2 Hz), 7.27-7.30 (3H, m), 6.98(1H, d, J=8.8 Hz), 6.82 (1H, dd, J=2.3 Hz, 8.8 Hz), 3.98 (2H, t, J=6.5Hz), 3.86 (3H, s), 2.99 (2H, t, J=6.5 Hz), 2.77 (2H, q, J=7.6 Hz), 1.33(3H, t, J=7.6 Hz).

[1405] Step 5.1-[4-(2-Chloroethyl)phenyl]-2-ethyl-5-methoxy-1H-benzimidazole

[1406] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-5-methoxy-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1407]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.2 Hz), 7.26-7.33 (3H, m), 6.99(1H, d, J=8.8 Hz), 6.82 (1H, dd, J=2.5 Hz, 8.8 Hz), 3.86 (3H, s), 3.81(2H, t, J=7.2 Hz), 3.18 (2H, t, J=7.2 Hz), 2.78 (2H, q, J=7.6 Hz), 1.34(3H, t, J=7.6 Hz).

[1408] Step 6. 1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylmethyl ether

[1409] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-methoxy-1H-benzimidazole (step 5).

[1410]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.4 Hz), 7.27-7.32 (3H, m), 6.98(1H, d, J=8.8 Hz), 6.82 (1H, dd, J=2.3 Hz, 8.8 Hz), 3.87 (3H, s), 3.61(2H, t, J=6.9 Hz), 3.01 (2H, t, J=6.9 Hz), 2.76 (2H, q, J=7.7 Hz), 1.34(3H, t, J=7.7 Hz).

[1411] Step 7.2-[4-(2-Ethyl-5-methoxy-1H-benzimidazol-1-yl)phenyl]ethylamine

[1412] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl methyl ether(step 6).

[1413]¹H-NMR (CDCl₃) δ 7.39 (2H, d, J=8.2 Hz), 7.26-7.30 (3H, m), 6.99(1H, d, J=8.7 Hz), 6.82 (1H, dd, J=2.3 Hz, 8.7 Hz), 3.86 (3H, s), 3.07(2H, t, J=6.9 Hz), 2.84 (2H, t, J=6.9 Hz), 2.77 (2H, q, J=7.6 Hz), 1.34(3H, t, J=7.6 Hz).

[1414] Step 8.5-Methoxy-2-Ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1415] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-5-methoxy-1H-benzimidazol-1-yl)phenyl]ethylamine (step 7).

[1416]¹H-NMR (CDCl₃) δ 7.74 (2H, d, J=8.2 Hz), 7.23-7.34 (7H, m), 6.97(1H, d, J=8.7 Hz), 6.82 (1H, dd, J=1.8 Hz, 8.7 Hz), 6.67 (1H, br.s),3.86 (3H, s), 3.57 (2H, t, J=6.4 Hz), 2.92 (2H, t, 6.4 Hz), 2.75 (2H, q,J=7.6 Hz), 2.40 (3H, s), 1.31 (3H, t, J=7.6 Hz).

Example 725-Methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1417] The title compound was prepared according to the proceduredescribed in Example 2 from5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 72).

[1418] mp 163-175° C.; ¹H-NMR (DMSO-d₆) δ 7.60 (2H, d, J=7.5 Hz),7.34-7.41 (4H, m), 7.12-7.18 (3H, m), 6.97 (1H, d, J=8.7 Hz), 6.78 (1H,d, J=8.7 Hz), 3.78 (3H, s), 2.66-2.76 (4H, m), 2.50 (2H, br.s), 2.78(3H, s), 1.22 (3H, t, J=7.6 Hz); IR (KBr) ν_(max) 3363, 2833, 1596,1404, 1128, 1085, 1026, 950 cm⁻¹.

Example 732-[4-(2-Ethyl-5-methoxy-1H-benzimidazole-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[1419] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(2-ethyl-5-methoxy-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 ofExample 71)

[1420] mp 95-98° C.; MS (ESI) m/z 494 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.93 (2H,d, J=8.2 Hz), 7.23-7.30 (3H, m), 7.16 (2H, d, J=8.2 Hz), 7.06 (2H, d,J=8.3 Hz), 6.92 (1H, d, J=8.8 Hz), 6.81 (1H, dd, J=2.2 Hz, 8.6 Hz), 4.33(2H, t, J=6.3 Hz), 3.84 (3H, s), 2.93 (2H, t, J=6.3 Hz), 2.68 (2H, q,J=7.5 Hz), 2.37 (3H, s), 1.22 (3H, t, J=7.5 Hz); IR (KBr) ν_(max) 1743,1596, 1517, 1487, 1444, 1278, 1159, 1074, 813 cm⁻¹.

Example 742-Ethyl-6-methoxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1421] Step 1. 2-[(5-Methoxy-2-nitroanilino)phenyl]ethanol

[1422] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2-chloro-4-methoxynitrobenene and4-aminophenylethyl alcohol.

[1423]¹H-NMR (CDCl₃) δ 9.74 (1H, br.s), 8.18 (1H, d, J=9.5 Hz), 7.30(2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 6.55 (1H, d, J=2.8 Hz), 6.34(1H, dd, J=9.5, 2.8 Hz), 3.90 (2H, m), 3.74 (3H, s), 2.90 (3H, t, J=6.6Hz).

[1424] Step 2. 2-[(2-Amino-5-methoxyanilino)phenyl]ethanol

[1425] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[(5-methoxy-2-nitroanilino)phenyl]ethanol (step 1).

[1426]¹H-NMR (CDCl₃) δ 7.09 (2H, d, J=8.4 Hz), 6.80 (2H, d, J=8.4 Hz),6.76-6.73 (2H, m), 6.54 (1H, dd, J=8.6, 2.8 Hz), 3.81 (2H, t, J=6.6 Hz),3.71 (3H, s), 2.79 (2H, t, J=6.6 Hz).

[1427] Step 3. 2-[4-(2-Ethyl-6-methoxy-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1428] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[(2-amino-5-methoxyanilino)phenyl]ethanol (step 2) and propionylchloride.

[1429] MS (EI) m/z 352 (M⁺).

[1430] Step 4.2-[4-(2-Ethyl-6-methoxy-1H-benzimidazol-1-yl)phenyl]ethanol

[1431] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-6-methoxy-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1432]¹H-NMR (CDCl₃) δ 7.63 (1H, d, J=8.8 Hz), 7.45 (2H, d, J=8.3 Hz),7.29 (2H, d, J=8.3 Hz), 6.89 (1H, dd, J=8.8, 2.6 Hz), 6.56 (1H, d, J=2.6Hz), 4.00 (2H, t, J=6.6 Hz), 3.75 (3H, s), 3.01 (2H, t, J=6.6 Hz), 2.74(2H, q, J=7.5 Hz), 1.32 (3H, t, J=7.5 Hz).

[1433] Step 5. 2-[4-(2-Ethyl-6-methoxy-1H-benzimidazol-1-yl)phenyl]ethylazide

[1434] The title compound was prepared according to the proceduredescribed in step 4 of Example 26 from2-(4-(2-ethyl-6-methoxy-1H-benzimidazol-1-yl)phenyl)ethanol (step 4).

[1435] TLC Rf=0.50 (hexane/ethyl acetate=1:1).

[1436] Step 6.2-[4-(2-Ethyl-6-methoxy-1H-benzimidazol-1-yl)phenyl]ethylamine

[1437] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-6-methoxy-1H-benzimidazol-1-yl)phenyl]ethyl azide (step5).

[1438]¹H-NMR (CDCl₃) δ 7.65 (1H, d, J=8.8 Hz), 7.41 (2H, d, J=8.3 Hz),7.29 (2H, d, J=8.3 Hz), 6.89 (1H, dd, J=8.8, 2.4 Hz), 6.56 (1H, d, J=2.4Hz), 3.76 (3H, s), 3.09 (2H, t, J=7.0 Hz), 2.89 (2H, t, J=7.0 Hz), 2.75(2H, q, J=7.5 Hz), 1.32 (3H, t, J=7.5 Hz).

[1439] Step 7.2-Ethyl-6-methoxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1440] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-6-methoxy-1H-benzimidazol-1-yl)phenyl]ethylamine (step 6).

[1441]¹H-NMR (CDCl₃) δ 7.75 (2H, d, J=8.2 Hz), 7.62 (1H, d, J=8.7 Hz),7.35-7.23 (6H, m), 6.89 (1H, dd, J=8.7, 2.5 Hz), 6.66 (1H, m), 6.55 (1H,d, J=2.5 Hz), 3.72 (3H, s), 3.59-3.57 (2H, m), 2.93 (2H, t, J=7.0 Hz),2.73 (2H, q, J=7.6 Hz), 1.29 (3H, t, J=7.6 Hz).

Example 752-Ethyl-6-methoxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1442] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-6-methoxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 74).

[1443]¹H-NMR (DMSO-d₆) δ 7.59 (2H, d, J=8.3 Hz), 7.50 (1H, d, J=8.8 Hz),7.41-7.35 (4H, m), 7.12 (2H, d, J=8.3 Hz), 6.80 (1H, dd, J=8.8, 2.4 Hz),6.53 (1H, d, J=2.4 Hz), 3.67 (3H, s), 3.15 (2H, m), 2.73-2.62 (4H, m),1.19 (3H, t, J=7.7 Hz); IR (KBr) ν_(max) 1595, 1516, 1485, 1454, 1400,1157, 1128, 1086 cm⁻¹.

Example 765-Trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1444] Step 1. 2-[2-Nitro-4-(trifluoromethyl)anilino]phenyl}ethanol

[1445] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from2-chloro-5-trifluoromethylnitrobenzene and 4-aminophenylethyl alcohol.

[1446]¹H-NMR (CDCl₃) δ 9.68 (1H, br.s), 8.50 (1H, s), 7.51 (1H, dd,J=2.2 Hz, 9.2 Hz), 7.33 (2H, d, J=8.2 Hz), 7.19-7.26 (3H, m), 3.92 (2H,t, J=6.3 Hz), 2.92 (2H, t, J=6.3 Hz).

[1447] Step 2. 2-[2-Amino-4-(trifluoromethyl)anilino]phenyl}ethanol

[1448] The title compound was prepared according to the proceduredescribed in step 2 of Example 26 from2-[2-nitro-4-(trifluoromethyl)anilino]phenyl}ethanol (step 1).

[1449]¹H-NMR (CDCl₃) δ 7.10-7.16 (3H, m), 6.97 (2H, d, J=8.2 Hz), 6.82(2H, d, J=8.2 Hz), 3.82 (2H, t, J=6.6 Hz), 2.79 (2H, t, J=6.6 Hz).

[1450] Step 3.2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylpropionate

[1451] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[2-amino-4-(trifluoromethyl)anilino]phenyl}ethanol (step 2) andpropionyl chloride.

[1452]¹H-NMR (CDCl₃) δ 8.05 (1H, s), 7.42-7.47 (2H, m), 7.27-7.31 (2H,m), 7.13 (2H, d, J=8.4 Hz), 4.39 (2H, t, J=7.0 Hz), 3.08 (2H, t, J=7.0Hz), 2.80 (2H, q, J=7.6 Hz), 2.36 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6Hz), 1.14 (3H, t, J=7.6 Hz).

[1453] Step 4.2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[1454] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylpropionate (step 3).

[1455]¹H-NMR (CDCl₃) δ 8.05 (1H, s), 7.49 (1H, d, J=8.4 Hz), 7.44 (2H,d, J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz), 7.16 (1H, d, J=8.4 Hz), 4.01 (2H,t, J=6.4 Hz), 3.03 (2H, t, J=6.4 Hz), 2.80 (2H, q, J=7.6 Hz), 1.36 (3H,t, J=7.6 Hz).

[1456] Step 5.2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazol-1yl]phenyl}ethyl azide

[1457] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-{4-[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 4).

[1458]¹H-NMR (CDCl₃) δ: 8.05 (1H, s), 7.22-7.48 (5H, m), 7.15 (1H, d,J=8.4 Hz), 3.62 (2H, t, J=6.8 Hz), 3.02 (2H, t, J=6.8 Hz), 2.80 (2H, q,J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz).

[1459] Step 6.2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazol-1yl]phenyl}ethylamine

[1460] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-{4-[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1yl]phenyl}ethyl azide(step 5).

[1461]¹H-NMR (CDCl₃) δ 8.05 (1H, s), 7.44 (3H, d, J=8.8 Hz), 7.29 (2H,d, J=8.8 Hz), 7.16 (1H, d, J=8.6 Hz), 3.09 (2H, t, J=6.8 Hz), 2.89 (2H,t, J=6.8 Hz), 2.81 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).

[1462] Step 7.5-Trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethy}phenyl)-1H-benzimidazole

[1463] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-{4-[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1yl]phenyl}ethylamine(step 6).

[1464] MS (ESI) m/z 533 (M+H)⁺; ¹H-NMR (CDCl₃) δ 8.03 (1H, s), 7.80 (2H,d, J=8.2 Hz), 7.73 (2H, d, J=8.2 Hz), 7.38-7.43 (3H, m), 7.26-7.29 (2H,m), 7.13 (1H, d, J=8.4 Hz), 6.70 (1H, br.s), 3.57 (2H, t, 6.7 Hz), 2.94(2H, t, J=6.7 Hz), 2.80 (2H, q, J=7.6 Hz), 2.43 (3H, s), 1.34 (3H, t,J=7.6 Hz).

Example 775-Trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1465] The title compound was prepared according to the proceduredescribed in Example 2 from5-trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 76).

[1466]¹H-NMR (DMSO-d₆) δ 8.02 (1H, s), 7.61-7.66 (4H, m), 7.48-7.51 (1H,m), 7.24-7.28 (3H, m), 7.14 (2H, d, 7.9 Hz), 3.09 (2H, br.s), 2.60-2.83(4H, m), 2.22 (3H, s), 1.13 (3H, t, J=7.5 Hz).

Example 785-Acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1467] Step 1. 1-{4-[4-(2-Hydroxyethyl)anilino]-3-nitrophenyl}ethanone

[1468] A mixture of 2-chloro-5-acetylnitrobenzene (Oelschlaeger, H.;Schreiber, O. Liebigs Ann. Chem., 1961, 641, 81., 2 g, 10 mmol),4-aminophenylethyl alcohol (1.64 g, 12 mmol) and NaHCO₃ (1 g, 12 mmol)in DMF (60 mL) was heated at 150° C. for 3 h. After cooling, the mixturewas poured into water (100 mL) and extracted with ethyl acetate (300mL). The organic layer was washed with 2N aqueous NaOH (100 mL) andbrine (100 mL), then dried (Na₂SO₄), and concentrated. Purification byflash column chromatography on silica gel eluting with hexane/ethylacetate (1:1) to afford 1.36 g (45%) of the title compound as an orangeoil; ¹H-NMR (CDCl₃) δ 9.83 (1H, br.s), 8.20 (1H, d, J=2.1 Hz), 7.94 (1H,dd, J=2.1 Hz, 9.3 Hz), 7.34 (2H, d, J=8.2 Hz), 7.24 (2H, d, J=8.2 Hz),7.16 (1H, d, J=9.3 Hz), 3.91 (2H, t, J=6.6 Hz), 2.92 (2H, t, J=6.6 Hz),2.57 (3H, s).

[1469] Step 2. 1-{3-Amino-4-[4-(2-hydroxyethyl)anilino]phenyl}ethanone

[1470] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from1-{4-[4-(2-hydroxyethyl)anilino]-3-nitrophenyl}ethanone (step 1).

[1471]¹H-NMR (CDCl₃) δ: 7.41 (1H, d, J=2.0 Hz), 7.37 (1H, dd, J=2.0 Hz,8.2 Hz), 7.11-7.17 (3H, m), 6.94 (2H, d, J=8.2 Hz), 5.72 (1H, br.s),3.85 (2H, t, J=6.6 Hz), 3.65 (2H, br.s), 2.83 (2H, t, J=6.6 Hz), 2.52(3H, s).

[1472] Step 3. 2-4-(5-Acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl)ethylpropionate

[1473] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-{3-amino-4-[4-(2-hydroxyethyl)anilino]phenyl}ethanone (step 2) andpropionyl chloride.

[1474] TLC Rf=0.4 (hexane/ethyl acetate=1:1).

[1475] Step 4.1-{2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}ethylpropionate

[1476] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl)ethyl propionate (step3).

[1477]¹H-NMR (CDCl₃) δ 8.39 (1H, d, J=1.2 Hz), 7.89 (1H, dd, J=1.2 Hz,8.6 Hz), 7.48 (2H, d, J=7.4 Hz), 7.30 (2H, d, J=7.4 Hz), 7.13 (1H, d,J=8.6 Hz), 4.00 (2H, t, J=6.4 Hz), 3.02 (2H, t, J=6.4 Hz), 2.80 (2H, q,J=7.6 Hz), 2.68 (3H, s), 1.38 (2H, t, J=7.6 Hz).

[1478] Step 5.1-{1-[4-(2-Chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}ethanone

[1479] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}ethanone(step 4).

[1480]¹H-NMR (CDCl₃) δ 8.40 (1H, d, J=1.2 Hz), 7.90 (1H, dd, J=1.2 Hz,8.4 Hz), 7.47 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.4 Hz), 7.13 (1H, d,J=8.4 Hz), 3.83 (2H, t, J=7.3 Hz), 3.21 (2H, t, J=7.3 Hz), 2.82 (2H, q,J=7.6 Hz), 2.68 (3H, s), 1.38 (3H, t, J=7.6 Hz).

[1481] Step 6.1-{1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}ethanone

[1482] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-{1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}ethanone(step 5).

[1483]¹H-NMR (CDCl₃) δ 8.40 (1H, d, J=1.5 Hz), 7.90 (1H, dd, J=1.5 Hz,8.6 Hz), 7.46 (2H, d, J=8.3 Hz), 7.12 (2H, d, J=8.3 Hz), 7.02 (1H, d,J=8.6 Hz), 3.63 (2H, t, J=6.9 Hz), 3.03 (2H, t, J=6.9 Hz), 2.80 (2H, q,J=7.4 Hz), 2.67 (3H, s), 1.37 (3H, t, J=7.4 Hz).

[1484] Step 7.1-{1-[4-(2-Aminoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}ethanone

[1485] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-{1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}ethanone(step 6).

[1486]¹H-NMR (CDCl₃) δ 8.40 (1H, d, J=1.7 Hz), 7.90 (1H, dd, J=1.7 Hz,8.6 Hz), 7.43 (2H, d, J=8.2 Hz), 7.30 (2H, d, J=8.2 Hz), 7.13 (1H, d,J=8.6 Hz), 3.08 (2H, t, J=6.7 Hz), 2.88 (2H, t, J=6.7 Hz), 2.80 (2H, q,J=7.6 Hz), 2.68 (3H, s), 1.38 (3H, t, J=7.6 Hz).

[1487] Step 8.5-Acetyl-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1488] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-{1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}ethanone(step 7).

[1489] MS (ESI) m/z 505 (M+H)⁺; ¹H-NMR CDCl₃) δ 8.40 (1H, d, J=1.1 Hz),7.88 (1H, dd, J=1.1 Hz, 8.6 Hz), 7.73 (2H, d, J=8.4 Hz), 7.40 (2H, d,J=8.4 Hz), 7.27-7.31 (4H, m), 7.10 (1H, d, J=8.6 Hz), 6.74 (1H, br.s),3.59 (2H, t, J=6.9 Hz), 2.95 (2H, t, J=6.9 Hz), 2.80 (2H, q, J=7.6 Hz),2.67 (3H, s), 2.40 (3H, s), 1.36 (3H, t, J=7.6 Hz).

Example 795-Acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1490] The title compound was prepared according to the proceduredescribed in Example 2 from5-acetyl-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 78).

[1491] mp 155-160° C.; ¹H-NMR (DMSO-d₆) δ 8.32 (1H, d, J=1.6 Hz), 7.81(1H, dd, J=1.6 Hz, 8.6 Hz), 7.62 (2H, d, J=8.1 Hz), 7.42 (4H, s),7.12-7.17 (3H, m), 3.18 (2H, br.s), 2.71-2.79 (4H, m), 2.63 (3H, s),2.27 (3H, s), 1.25 (3H, t, J=7.4 Hz); IR (KBr) ν_(max) 3373, 1676, 1604,1519, 1294, 1130, 1085, 885, 813 cm⁻¹.

Example 802-Ethyl-5-methylsulfonyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1492] Step 1. 2-{4-[4-(Methylsulfonyl)-2-nitroanilino]phenyl}ethanol

[1493] A mixture of 2-chloro-5-methylsulfonylnitrobenzene (Kavalek, J.;et al. Collect. Czech. Chem. Commun, 1971, 36, 209., 2 g, 8.5 mmol),4-aminophenylethyl alcohol (1.4 g, 10.2 mmol) and Na₂CO₃ (1.4 g, 12.7mmol) in ethanol was stirred at 100° C. for 16 h. The insoluble matterwas removed by filtration and washed with ethanol (100 mL). The filtratewas concentrated and the residue was purified by flash columnchromatography on silica gel eluting with hexane/ethyl acetate (1:4) toafford 960 mg (34%) of the title compound as yellow solids: ¹H-NMR(CDCl₃) δ 9.84 (1H, br.s), 8.82 (1H, d, J=2.1 Hz), 7.79 (1H, dd, J=2.1Hz, 9.1 Hz), 7.36 (2H, d, J=8.4 Hz), 7.22-7.38 (3H, m), 3.94 (2H, br.s),3.07 (3H, s), 2.93 (2H, t, J=6.6 Hz).

[1494] Step 2. 2-{4-[2-Amino-4-(methylsulfonyl)anilino]phenyl}ethanol

[1495] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{4-[4-(methylsulfonyl)-2-nitroanilino]phenyl}ethanol (step 1).

[1496]¹H-NMR (CDCl₃) δ 7.31 (1H, s), 7.28 (1H, s), 7.16-7.21 (3H, m),6.96 (2H, d, J=8.5 Hz), 5.56 (1H, br.s), 3.86 (2H, t, J=6.4 Hz), 3.76(2H, br.s), 3.03 (3H, s), 2.84 (2H, t, J=6.4 Hz).

[1497] Step 3.2-{4-[2-Ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethylpropionate

[1498] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[2-amino-4-(methylsulfonyl)anilino]phenyl}ethanol (step 2) andpropionyl chloride.

[1499] TLC Rf=0.8 (dichloromethane/methanol=10:1).

[1500] Step 4.2-{4-[2-Ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[1501] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethylpropionate (step 3).

[1502]¹H-NMR (CDCl₃) δ 8.38 (1H, d, J=1.4 Hz), 7.77 (1H, dd, J=1.4 Hz,8.6 Hz), 7.50 (2H, d, J=8.4 Hz), 7.24-7.32 (2H, m), 7.22 (1H, d, J=8.6Hz), 4.01 (t, J=6.6 Hz), 3.08 (3H, s), 3.02 (2H, t, J=6.6 Hz), 2.82 (2H,q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).

[1503] Step 5.1-[4-(2-Chloroethyl)phenyl]-2-ethyl-5-(methylsulfonyl)-1H-benzimidazole

[1504] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-{4-[2-ethyl-5-(methylsulfonyl)-H-benzimidazol-1-yl]phenyl}ethanol(step 4).

[1505]¹H-NMR (CDCl₃) δ 8.38 (1H, d, J=1.6 Hz), 7.78 (1H, d, J=1.6 Hz,8.6 Hz), 7.49 (2H, d, J=8.1 Hz), 7.32 (2H, d, J=8.1 Hz), 7.23 (1H, d,J=8.6 Hz), 3.84 (2H, t, J=6.9 Hz), 3.22 (2H, t, J=6.9 Hz), 3.08 (3H, s),2.82 (2H, q, J=7.5 Hz), 1.38 (3H, t, J=7.5 Hz).

[1506] Step 6. 1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylmethyl sulfone

[1507] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-(methylsulfonyl)-1H-benzimidazole(step 5).

[1508]¹H-NMR (CDCl₃) δ 8.38 (1H, d, J=1.5 Hz), 7.78 (1H, dd, J=1.5 Hz,8.6 Hz), 7.49 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.4 Hz), 7.21 (1H, d,J=8.6 Hz), 3.64 (2H, t, J=6.9 Hz), 3.08 (3H, s), 3.03 (2H, t, J=6.9 Hz),2.83 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).

[1509] Step 7.2-{4-[2-Ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethylamine

[1510] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl methyl sulfone(step 6).

[1511]¹H-NMR (CDCl₃) δ 8.38 (1H, d, J=1.7 Hz), 7.77 (1H, dd, J=1.7 Hz,8.6 Hz), 7.46 (2H, d, J=8.4 Hz), 7.21-7.30 (3H, m), 3.03-3.08 (5H, m),2.89 (2H, t, J=6.7 Hz), 2.82 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).

[1512] Step 8.2-Ethyl-5-(methylsulfonyl)-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1513] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-{4-[2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethylamine(step 7).

[1514]¹H-NMR (CDCl₃) δ 8.37 (1H, d, J=1.6 Hz), 7.75 (1H, dd, J=1.6 Hz,8.6 Hz), 7.74 (2H, d, J=8.4 Hz), 7.43 (2H, d, J=8.2 Hz), 7.27-7.32 (4H,m), 7.18 (1H, d, J=8.6 Hz), 6.70 (1H, br.s), 3.59 (2H, t, J=6.8 Hz),3.08 (3H, s), 2.96 (2H, t. J=6.8 Hz), 2.82 (2H, q, J=7.6 Hz), 2.41 (3H,s), 1.35 (4H, t, J=7.6 Hz).

Example 812-Ethyl-5-methylsulfonyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1515] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-5-(methylsulfonyl)-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 80).

[1516] mp 171-178° C.; ¹H-NMR (DMSO-d₆) δ 8.08 (1H, br.s), 7.51-7.62(3H, m), 7.32 (4H, s), 7.16 (1H, d, J=8.6 Hz), 7.03 (2H, d, J=7.3 Hz),3.09-3.25 (7H, m), 2.63-2.66 (2H, m), 2.16 (3H, s), 1.13 (3H, t, J=7.3Hz); IR (KBr) ν_(max) 3386, 1604, 1519, 1396, 1299, 1128, 1085, 962, 887cm⁻¹.

Example 825-Cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1517] Step 1. 2-[(4-Cyano-2-nitroanilino)phenyl]ethanol

[1518] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 4-chloro-3-nitrobenzonitrile and4-aminophenylethyl alcohol.

[1519]¹H-NMR (CDCl₃) δ 9.80 (1H, br.s), 8.54 (1H, d, J=2.0 Hz), 7.50(1H, dd, J=9.1, 2.0 Hz), 7.36 (2H, d, J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz),7.16 (1H, d, J=9.1 Hz), 3.94-3.91 (2H, m), 2.93 (2H, t, J=6.6 Hz), 1.81(1H, m).

[1520] Step 2. 2-[(2-Amino-4-cyanoanilino)phenyl]ethanol

[1521] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[(4-cyano-2-nitroanilino)phenyl]ethanol (step 1).

[1522]¹H-NMR (CDCl₃) δ 7.18-7.10 (3H, m), 7.01-6.95 (4H, m), 6.09 (1H,m), 3.97 (2H, br.s), 3.83-3.82 (2H, m), 2.83 (2H, t, J=6.8 Hz), 2.31(1H, m)

[1523] Step 3. 2-[4-(5-Cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1524] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[(2-amino-4-cyanoanilino)phenyl]ethanol (step 2).

[1525] MS (EI) m/z 347 (M⁺).

[1526] Step 4. 2-[4-(5-Cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1527] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step3).

[1528]¹H-NMR (CDCl₃) δ 8.09 (1H, s), 7.50-7.43 (3H, m), 7.32-7.28 (2H,m), 7.15 (1H, d, J=8.2 Hz), 4.00 (2H, q, H=6.4 Hz), 3.01 (2H, t, J=6.4Hz), 2.81 (2H, t, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).

[1529] Step 5. 2-[4-(5-Cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1530] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1531] TLC Rf=0.83 (dichloromethane/methanol=10:1).

[1532] Step 6.2-[4-(5-Cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1533] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 5).

[1534]¹H-NMR (CDCl₃) δ 8.09 (1H, s), 7.47-7.42 (3H, m), 7.29-7.26 (2H,m), 7.15 (1H, d, J=8.4 Hz), 3.09 (2H, t, J=6.8 Hz), 2.91 (2H, t, J=6.8Hz), 2.81 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).

[1535] Step 7.5-Cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1536] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 6).

[1537]¹H-NMR (CDCl₃) δ 8.05 (1H, d, J=0.9 Hz), 7.75 (2H, d, J=8.4 Hz),7.43-7.40 (3H, m), 7.30-7.26 (4H, m), 7.12 (1H, d, J=8.4 Hz), 6.74 (1H,m), 3.60-3.58 (2H, m), 2.96 (2H, t, J=7.0 Hz), 2.81 (2H, q, J=7.5 Hz),2.41 (3H, s), 1.34 (3H, t, J=7.5 Hz).

Example 835-Cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1538] The title compound was prepared according to the proceduredescribed in Example 2 from5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 82).

[1539]¹H-NMR (DMSO-d₆) δ 8.19 (1H, d, J=1.5 Hz), 7.59 (2H, d, J=7.9 Hz),7.54 (1H, dd, J=8.4, 1.5 Hz), 7.41 (4H, s), 7.23 (1H, d, J=8.4 Hz), 7.11(2H, d, J=7.9 Hz), 3.14 (2H, m), 2.78-2.70 (4H, m), 2.26 (3H, s), 1.24(3H, t, J=7.4 Hz).

Example 842-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

[1540] Step 1.2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide

[1541] To a mixture of2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 ofExample 82, 200 mg, 0.68 mmol), DMSO (0.06 mL, 0.82 mmol) and methanol(10 mL) was added 30% aqueous solution of hydrogen peroxide (0.12 mL,1.0 mmol) and 0.2 M aqueous NaOH (0.06 mL). The mixture was stirred at50° C. for 4 h, then cooled. The mixture was poured into water (50 mL)and extracted with ethyl acetate (100 mL). The organic layer was washedwith 2N aqueous NaOH (50 mL) and brine (50 mL), then dried (Na₂SO₄), andconcentrated to afford the title compound as pale yellow solids: ¹H-NMR(CDCl₃) δ 8.23 (1H, d, J=1.1 Hz), 7.96 (1H, br.s), 7.76 (1H, dd, J=1.1Hz, 8.4 Hz), 7.42-7.51 (4H, m), 7.25 (1H, br.s), 7.09 (1H, d, J=8.4 Hz),3.70 (2H, t, J=6.6 Hz), 2.85 (2H, t, J=6.9 Hz), 2.76 (2H, q, J=7.4 Hz),1.24 (3H, t, J=7.4 Hz).

[1542] Step 2.1-[4-(2-Chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide

[1543] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide(step 1).

[1544]¹H-NMR (CDCl₃) δ 8.17 (1H, d, J=1.7 Hz), 7.79 (1H, dd, J=1.7 Hz,8.5 Hz), 7.46 (2H, d, J=8.3 Hz), 7.33 (2H, d, J=8.3 Hz), 7.15 (1H, d,J=8.5 Hz), 3.83 (2H, t, J=7.0 Hz), 3.21 (2H, t, J=7.0 Hz), 2.82 (2H, q,J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).

[1545] Step 3.1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide

[1546] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide (step2).

[1547]¹H-NMR (CDCl₃) δ 8.17 (1H, d, J=1.5 Hz), 7.78 (1H, dd, J=1.5 Hz,8.4 Hz), 7.46 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.13 (1H, d,J=8.4 Hz), 3.62 (2H, t, J=6.8 Hz), 3.03 (2H, t, J=6.8 Hz), 2.81 (2H, q,J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz).

[1548] Step 4.1-[4-(2-Aminoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide

[1549] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide (step3).

[1550]¹H-NMR (CDCl₃) δ 8.21 (1H, d, J=1.5 Hz), 7.79 (1H, dd, J=1.5 Hz,8.4 Hz), 7.43 (2H, d, J=8.2 Hz), 7.28-7.31 (2H, m), 7.13 (1H, d, J=8.4Hz), 3.05 (2H, t, J=6.7 Hz), 2.88 (2H, t, J=6.7 Hz), 2.81 (2H, q, J=7.6Hz), 1.35 (3H, t, J=7.6 Hz).

[1551] Step 5.2-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

[1552] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide (step4).

[1553] MS (ESI) m/z 506 (M+H)⁺; ¹H-NMR (CD₃OD) δ 8.13 (1H, s), 7.65-7.73(3H, m), 7.32 (2H, d, J=8.2 Hz), 7.16-7.21 (4H, m), 7.00 (1H, d, J=8.6Hz), 3.31 (2H, t, J=6.9 Hz), 2.75 (2H, t, J=6.9 Hz), 2.69 (2H, q, J=7.6Hz), 2.21 (3H, s), 1.48 (3H, t, J=7.6 Hz).

Example 856-Cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1554] Step 1. 3-[4-(2-Hydroxyethyl)anilino]-4-nitrobenzonitrile

[1555] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 3-chloro-4-nitrobenzonitrile(Tsuji, K. Chem. Pharm. Bull. 1992, 40, 2399) and 4-aminophenylethylalcohol.

[1556] MS (EI) m/z 383 (M⁺).

[1557] Step 2. 3-[4-(2-Chloroethyl)anilino]-4-nitrobenzonitrile

[1558] The title compound was prepared according to the proceduredescribed in step 7 Example 1 from3-[4-(2-hydroxyethyl)anilino]-4-nitrobenzonitrile (step 1).

[1559]¹H-NMR (CDCl₃) δ 9.46 (1H, br.s), 8.29 (1H, d, J=8.8 Hz), 7.42(1H, d, J=1.7 Hz), 7.35 (2H, d, J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz), 6.97(1H, dd, J=8.8, 1.7 Hz), 3.77 (2H, t, J=7.2 Hz), 3.13 (2H, t, J=7.2 Hz).

[1560] Step 3. 4-Amino-3-[4-(2-chloroethyl)anilino]benzonitrile

[1561] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from3-[4-(2-chloroethyl)anilino]-4-nitrobenzonitrile (step 2).

[1562] MS (EI) m/z 383 (M⁺).

[1563] Step 4.1-[4-(2-Chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-6-carbonitrile

[1564] The title compound was prepared according to the proceduredescribed in step 5 Example 1 from4-amino-3-[4-(2-chloroethyl)anilino]benzonitrile (step 3) and propionylchloride.

[1565] MS (EI) m/z 309 (M⁺); ¹H-NMR (CDCl₃) δ 7.82 (1H, d, J=8.6 Hz),7.53 (1H, dd, J=8.6, 2.0 Hz), 7.48 (2H, d, J=8.3 Hz), 7.42 (1H, d, J=2.0Hz), 7.31 (2H, d, J=8.3 Hz), 3.84 (2H, t, J=7.0 Hz), 3.21 (2H, t, J=7.0Hz), 2.82 (2H, q, J=7.4 Hz), 1.39 (3H, t, J=7.4 Hz).

[1566] Step 5. 2-[4-(6-Cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1567] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-6-carbonitrile(step 4).

[1568] MS (EI) m/z 316 (M⁺); ¹H-NMR (CDCl₃) δ 7.83 (1H, d, J=8.4 Hz),7.54 (1H, dd, J=8.4, 2.0 Hz), 7.50 (2H, d, J=8.3 Hz), 7.40 (1H, d, J=2.0Hz), 7.30 (2H, d, J=8.3 Hz), 3.64 (2H, t, J=6.5 Hz), 3.04 (2H, t, J=6.5Hz), 2.83 (2H, q, J=7.3 Hz), 1.37 (3H, t, J=7.3 Hz).

[1569] Step 6.2-[4-(6-Cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1570] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(6-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 5).

[1571]¹H-NMR (DMSO-d₆) δ 8.11 (2H, br.s), 7.87 (1H, d, J=8.4 Hz), 7.64(1H, dd, J=8.4, 2.0 Hz), 7.60-7.53 (5H, m), 3.20-3.02 (4H, m), 2.79 (2H,q, J=7.4 Hz), 1.28 (3H, t, J=7.4 Hz).

[1572] Step 7.6-Cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1573] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(6-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 6).

[1574]¹H-NMR (CDCl₃) δ 7.83 (1H, d, J=8.4 Hz), 7.74 (2H, d, J=8.4 Hz),7.53 (1H, dd, J=8.4, 1.5 Hz), 7.43 (2H, d, J=8.4 Hz), 7.39 (1H, d, J=1.5Hz), 7.33 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 6.75 (1H, br.s),3.65-3.54 (2H, m), 2.97 (2H, t, J=7.0 Hz), 2.82 (2H, q, J=7.5 Hz), 2.42(3H, s), 1.37 (3H, t, J=7.5 Hz).

Example 862-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-6-carboxamide

[1575] To a solution of6-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 85, 162 mg, 0.33 mmol) in 2-methyl-2-propanol (10 mL) was addedpowdered KOH (66 mg, 1.0 mmol). The resulting mixture was heated atreflux temperature for 3 h. After removal of solvent, the reactionmixture was partitioned between dichloromethane (50 mL) and phosphatebuffer (50 mL). The organic phase was separated and the aqueous phasewas extracted with dichloromethane (50 mL). The combined organic phaseswere washed with brine (50 mL), dried (Na₂SO₄), and concentrated. Theresidual solids were recrystallized from ethyl acetate to afford 105 mg(63%) of the title compound as white solids: ¹H-NMR (CDCl₃) δ: 7.79 (2H,d, J=8.4 Hz), 7.75 (1H, d, J=8.8 Hz), 7.71-7.63 (2H, m), 7.35-7.25 (4H,m), 7.16 (2H, d, J=8.4 Hz), 6.75 (2H, br.s), 6.55 (1H, br.s), 3.54 (2H,t, J=6.4 Hz), 2.88 (2H, t, J=6.4 Hz), 2.79 (2H, q, J=7.5 Hz), 2.40 (3H,s), 1.34 (3H, t, J=7.5 Hz).

Example 875-[(tert-Butylamino)sulfonyl]-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1576] Step 1. N-(tert-Butyl)-4-chloro-3-nitrobenzenesulfonamide

[1577] To a stirred solution of tert-butylamine (5.1 g, 70 mmol) indichloromethane (200 mL) was added dropwise a solution of4-chloro-3-nitrobenzenesulfonyl chloride (17.9 g, 70 mmol) indichloromethane (100 mL) at room temperature over a period of 30 min,and then the reaction mixture was stirred for 2 h. The reaction mixturewas poured into water (100 mL), the organic phase was separated, and theaqueous phase was extracted with ethyl acetate (100 mL). The combinedorganic extracts were washed with water (50 mL) and brine (20 mL), dried(Na₂SO₄), and concentrated to give 21.3 g (quant.) of the title compoundas yellow solids: ¹H-NMR (CDCl₃) δ 8.38 (1H, d, J=2.0 Hz), 8.02 (1H, dd,J=2.0, 8.6 Hz), 7.70 (1H, d, J=8.6 Hz), 4.95 (1H, br.s), 1.28 (9H, s).

[1578] Step 2.N-(tert-Butyl)-4-[4-(2-hydroxyethyl)anilino]-3-nitrobenzenesulfonamide

[1579] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 fromN-(tert-butyl)-4-chloro-3-nitrobenzenesulfonamide (step 1) and4-aminophenylethyl alcohol.

[1580] MS (EI) m/z 393 (M⁺); ¹H-NMR (CDCl₃) δ 9.76 (1H, br.s), 8.75 (1H,d, J=2.0 Hz), 7.74 (1H, dd, J=2.0, 8.5 Hz), 7.35 (2H, d, J=8.3 Hz), 7.24(2H, d, J=8.3 Hz), 7.17 (1H, d, J=8.5 Hz), 4.42 (1H, br.s), 3.97-3.88(2H, m), 2.94 (2H, t, J=7.0 Hz), 1.27 (9H, s).

[1581] Step 3.N-(tert-Butyl)-4-[4-(2-chloroethyl)anilino]-3-nitrobenzenesulfonamide

[1582] The title compound was prepared according to the proceduredescribed in step 7 Example 1 fromN-(tert-butyl)-4-[4-(2-hydroxyethyl)anilino]-3-nitrobenzenesulfonamide(step 2).

[1583] MS (EI) m/z 411 (M⁺); ¹H-NMR (CDCl₃) δ 9.77 (1H, br.s), 8.77 (1H,d, J=2.0 Hz), 7.77 (1H, dd, J=2.0, 8.4 Hz), 7.34 (2H, d, J=8.3 Hz), 7.25(2H, d, J=8.3 Hz), 7.18 (1H, d, J=8.4 Hz), 4.46 (1H, br.s), 3.76 (2H, t,J=6.8 Hz), 3.13 (2H, t, J=6.8 Hz), 1.28 (9H, s).

[1584] Step 4.3-Amino-N-(tert-butyl)-4-[4-(2-chloroethyl)anilino]benzenesulfonamide

[1585] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 fromN-(tert-butyl)-4-[4-(2-chloroethyl)anilino]-3-nitrobenzenesulfonamide(step 3).

[1586]¹H-NMR (CDCl₃) δ 7.31 (1H, d, J=2.0 Hz), 7.26 (1H, dd, J=2.0, 8.3Hz), 7.15 (1H, d, J=8.3 Hz), 7.14 (2H, d, J=8.4 Hz), 6.89 (2H, d, J=8.4Hz), 5.49 (1H, br.s), 4.64 (1H, br.s), 3.77 (2H, br.s), 3.69 (2H, t,J=7.4 Hz), 3.02 (2H, t, J=7.4 Hz), 1.24 (9H, s).

[1587] Step 5.N-(tert-Butyl)-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-sulfonamide

[1588] The title compound was prepared according to the proceduredescribed in step 5 Example 1 from3-amino-N-(tert-butyl)-4-[4-(2-chloroethyl)anilino]benzenesulfonamide(step 4) and propionyl chloride.

[1589] MS (EI) m/z 419 (M⁺); ¹H-NMR (CDCl₃) δ 8.34 (1H, d, J=2.0 Hz),7.74 (1H, dd, J=2.0, 8.3 Hz), 7.47 (2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.6Hz), 7.16 (1H, d, J=8.3 Hz), 4.62 (1H, br.s), 3.83 (2H, t, J=7.0 Hz),3.21 (2H, t, J=7.0 Hz), 2.82 (2H, q, J=7.4 Hz), 1.39 (3H, t, J=7.4 Hz)1.24 (9H, s).

[1590] Step 6.1-[4-(2-Azidoethyl)phenyl]-N-(tert-butyl)-2-ethyl-1H-benzimidazole-5-sulfonamide

[1591] The title compound was prepared according to the proceduredescribed in step 8 Example 1 fromN-(tert-butyl)-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-sulfonamide(step 5).

[1592] MS (EI) m/z 426 (M⁺); ¹H-NMR (CDCl₃) δ 8.33 (1H, d, J=2.0 Hz),7.73 (1H, dd, J=2.0, 8.4 Hz), 7.48 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4Hz), 7.14 (1H, d, J=8.4 Hz), 4.47 (1H, br.s), 3.62 (2H, t, J=7.0 Hz),3.03 (2H, t, J=7.0 Hz), 2.82 (2H, q, J=7.2 Hz), 1.38 (3H, t, J=7.2 Hz)1.24 (9H, s).

[1593] Step 7.1-[4-(2-Aminoethyl)phenyl]-N-(tert-butyl)-2-ethyl-1H-benzimidazole-5-sulfonamide

[1594] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from1-[4-(2-azidoethyl)phenyl]-N-(tert-butyl)-2-ethyl-1H-benzimidazole-5-sulfonamide(step 6).

[1595]¹H-NMR (CDCl₃) δ 8.34 (1H, d, J=1.9 Hz), 7.74 (1H, dd, J=1.9, 8.3Hz), 7.44 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.15 (1H, d, J=8.3Hz), 4.88 (1H, br.s), 3.09 (2H, t, J=7.0 Hz), 2.95 (2H, t, J=7.0 Hz),2.83 (2H, q, J=7.4 Hz), 1.37 (3H, t, J=7.4 Hz) 1.23 (9H, s).

[1596] Step 8.5-[(tert-Butylamino)sulfonyl]-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1597] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-[4-(2-aminoethyl)phenyl]-N-(tert-butyl)-2-ethyl-1H-benzimidazole-5-sulfonamide(step 7).

[1598] MS (ESI) m/z 598 (M+H)⁺; ¹H-NMR (CDCl₃) δ 8.32 (1H, d, J=1.3 Hz),7.77-7.69 (3H, m), 7.41(2H, d, J=8.3 Hz), 7.33-7.25 (4H, m), 7.11 (1H,d, J=8.6 Hz), 6.65 (1H, br.s), 4.59 (1H, s), 3.63-3.53 (2H, m), 2.95(2H, t, J=7.0 Hz), 2.80 (2H, q, J=7.6 Hz), 2.41 (3H, s), 1.36 (3H, t,J=7.6 Hz) 1.23 (9H, s).

Example 885-(Aminosulfonyl)-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1599] A solution of5-[(tert-butylamino)sulfonyl]-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 87, 330 mg, 0.55 mmol) in trifluoroacetic acid (10 mL) washeated at 80° C. for 2 h. The mixture was concentrated and the residuewas purified by flash chromatography on silica gel eluting withdichloromethane/methanol (10:1) to afford 215 mg (73%) of the titlecompound: MS (ESI) m/z 542 (M+H)⁺; ¹H-NMR (CDCl₃) δ 8.32 (1H, d, J=1.3Hz), 7.77-7.69 (3H, m), 7.41(2H, d, J=8.3 Hz), 7.33-7.25 (4H, m), 7.11(1H, d, J=8.6 Hz), 6.65 (1H, br.s), 4.59 (1H, s), 3.63-3.53 (2H, m),2.95 (2H, t, J=7.0 Hz), 2.80 (2H, q, J=7.6 Hz), 2.41 (3H, s), 1.36 (3H,t, J=7.6 Hz) 1.23 (9H, s).

Example 892-Ethyl-1-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-5-[(methylsulfonyl)amino]-1H-benzimidazole

[1600] Step 1. 2-[4-(2,4-Dinitroanilino)phenyl]ethanol

[1601] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2-chloro-1,5-dinitrobenzene and4-aminophenylethyl alcohol.

[1602]¹H-NMR (CDCl₃) δ 9.95 (1H, s), 9.18 (1H, d, J=2.4 Hz), 8.16 (1H,dd, J=2.7, 9.7 Hz), 7.39 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.1 Hz), 7.16(1H, d, J=9.5 Hz), 3.93 (2H, dt, J=5.7, 6.2 Hz), 2.94 (2H, t, J=6.8 Hz),1.50 (1H, t, J=5.7 Hz).

[1603] Step 2. 2-[4-(2-Amino-4-nitroanilino)phenyl]ethanol

[1604] The title compound was prepared according to the proceduredescribed in step 2 of Example 40 from2-[4-(2,4-dinitroanilino)phenyl]ethanol (step 1).

[1605]¹H-NMR (CDCl₃) δ 7.73-7.67 (2H, m), 7.22 (2H, d, J=8.3 Hz), 7.11(1H, d, J=9.3 Hz), 7.04 (2H, d, J=8.3 Hz), 5.80 (1H, s), 3.88 (2H, dt,J=5.7, 6.0 Hz), 3.69 (2H, br.s), 2.87 (2H, t, J=6.4 Hz), 1.48 (1H, br).

[1606] Step 3. 2-[4-(2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1607] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-4-nitroanilino)phenyl]ethanol (step 2) and propionylchloride.

[1608]¹H-NMR (CDCl₃) δ 8.68 (1H, d, J=2.2 Hz), 8.13 (1H, dd, J=2.2, 9.0Hz), 7.48 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 7.13 (1H, d, J=8.97Hz), 4.39 (2H, t, J=6.8 Hz), 3.09 (2H, t, J=7.0 Hz), 2.81 (2H, q, J=7.5Hz), 2.36 (2H, q, J=7.5 Hz), 1.38 (3H, t, J=7.5 Hz), 1.15 (3H, q, J=7.5Hz).

[1609] Step 4. 2-[4-(5-Amino-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1610] To a stirred solution of2-[4-(2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step3, 1.12 g, 3.0 mmol) in ethanol/water (v/v, 2:1, 15 mL) was addedammonium chloride (80 mg, 1.5 mmol) and iron powder (840 mg, 15 mmol) atroom temperature. The mixture was heated at reflux temperature for 4 hand filtered through a pad of Celite. The filtrate was concentrated, andthe residue was dissolved in dichloromethane (200 mL), then dried(MgSO₄). Removal of solvent gave 0.84 g (83%) of the title compound as ayellow oil: ¹H-NMR (CDCl₃) δ 7.41 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.6Hz), 7.10 (1H, d, J=1.8 Hz), 6.89 (1H, d, J=8.4 Hz), 6.63 (1H, dd,J=2.2, 8.4 Hz), 4.37 (2H, t, J=7.0 Hz), 3.05 (2H, t, J=7.1 Hz), 2.79(2H, q, J=7.5 Hz), 2.35 (2H, q, J=7.5 Hz), 1.33 (3H, t, J=7.50 Hz), 1.14(3H, t, J=7.7 Hz).

[1611] Step 5.2-(4-{2-Ethyl-5-[(methylsulfonyl)amino]-1H-benzimidazol-1-yl}phenyl)ethylpropionate

[1612] To a stirred solution of2-[4-(5-amino-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step4, 1.18 g, 3.50 mmol) in dichloromethane (20 mL) was addedmethanesulfonyl chloride (0.40 mL, 5.25 mmol) and pyridine (0.42 mL,5.25 mmol) at room temperature. After stirring for 6 h, the mixture waspoured into 10% aqueous citric acid (100 mL) and extracted with ethylacetate (100 mL). The aqueous layer was made basic with saturatedaqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate(100 mL). The combined organic extracts were washed with brine (100 mL)and dried (MgSO₄), and concentrated to afford 1.28 g (88%) of the titlecompound as brown amorphous: ¹H-NMR (CDCl₃) δ 8.47 (1H, s), 7.66 (1H, d,J=1.7 Hz), 7.50 (2H, d, J=8.4 Hz), 7.42 (1H, dd, J=2.0, 8.8 Hz), 7.41(2H, d, J=8.4 Hz), 7.09 (1H, d, J=8.8 Hz), 4.39 (2H, t, J=7.0 Hz), 3.09(2H, t, J=6.8 Hz), 3.00 (2H, q, J=7.7 Hz), 2.36 (2H, q, J=7.7 Hz), 1.42(3H, t, J=7.7 Hz), 1.15 (3H, t, J=7.5 Hz).

[1613] Step 6.2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}methanesulfonamide

[1614] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-(4-{2-ethyl-5-[(methylsulfonyl)amino]-1H-benzimidazol-1-yl}phenyl)ethylpropionate (step 5).

[1615]¹H-NMR (CDCl₃) δ 7.63 (1H, d, J=1.8 Hz), 7.46 (2H, d, J=8.2 Hz),7.29 (2H, d, J=8.4 Hz), 7.18 (1H, dd, J=2.1, 8.6 Hz), 7.07 (1H, d, J=8.6Hz), 6.68 (1H, br), 3.99 (2H, t, J=6.4 Hz), 3.01 (2H, t, J=6.8 Hz), 2.98(3H, s), 2.79 (2H, q, J=7.4 Hz), 1.35 (3H, t, J=7.6 Hz).

[1616] Step 7.N-{1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide

[1617] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}methanesulfonamide(step 6).

[1618]¹H-NMR (CDCl₃) δ 7.74-6.85 (7H, m), 3.83 (2H, t, J=7.1 Hz), 3.21(2H, t, J=7.1 Hz), 2.98 (3H, s), 2.85 (2H, q, J=7.5 Hz), 1.38 (3H, t,J=7.5 Hz).

[1619] Step 8.N-{1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide

[1620] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 fromN-{1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide(step 7).

[1621]¹H-NMR (CDCl₃) δ 7.64 (1H, br), 7.45 (2H, d, J=8.3 Hz), 7.31 (2H,d, J=8.1 Hz), 7.19 (1H, dd, J=1.8, 8.8 Hz), 7.07 (1H, d, J=8.4 Hz), 6.81(1H, s), 3.62 (2H, t, J=6.8 Hz), 3.02 (2H, t, J=7.0 Hz), 2.98 (3H, s),2.79 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.5 Hz).

[1622] Step 9.N-{1-[4-(2-Aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide

[1623] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 fromN-{1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide(step 8).

[1624] MS (EI) m/z 358 (M⁺).

[1625] Step 10.N-{1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide

[1626] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 fromN-{1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide(step 9).

[1627] MS (ESI) m/z 556 (M+H)⁺; ¹H-NMR (CDCl₃) δ 9.49 (1H, s), 7.76 (2H,d, J=7.1 Hz), 7.51 (1H, br), 7.42-7.34 (6H, m), 7.07 (1H, d, J=8.6 Hz),7.01 (1H, d, J=8.6 Hz), 6.53 (1H, br), 3.40-3.33 (2H, m), 2.89 (3H, s),2.81-2.66 (4H, m), 2.33 (3H, s), 1.21 (3H, t, J=7.5 Hz); IR (KBr)ν_(max) 1697, 1684, 1508, 1458, 1148 cm⁻¹.

Example 902-Ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1628] Step 1. 1-[4-(2-Bromoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ol

[1629] A mixture of1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-methoxy-1H-benzimidazole (step 5of Example 71, 600 mg, 1.9 mmol) in 48% hydrobromic acid (60 mL) wasstirred at 100° C. for 6 h. After cooling, the mixture was neutralizedwith 2N aqueous NaOH and extracted with ethyl acetate (100 mL). Theorganic layer was washed with brine (50 mL), dried (Na₂SO₄), andconcentrated to afford 890 mg (quant.) of the title compound as paleyellow solids: ¹H-NMR (CDCl₃) δ 7.64 (4H, s), 7.16 (2H, m), 6.97-7.01(1H, m), 3.86 (2H, t, J=7.1 Hz), 3.30 (2H, t, J=7.1 Hz), 2.92 (2H, q,J=7.8 Hz), 1.29 (3H, t, J=7.8 Hz).

[1630] Step 2. 1-[4-(2-Bromoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yltert-butyl(dimethyl)silyl ether

[1631] A mixture of1-[4-(2-bromoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ol (step 1, 200 mg,0.58 mmol), tert-butyldimethylsilyl chloride (100 mg, 0.7 mmol) andimidazole (47 mg, 1.45 mmol) in DMF (5 mL) was stirred at roomtemperature for 3 h. The reaction mixture was poured into water (50 mL),and extracted with ethyl acetate (100 mL). The organic layer was washedwith brine (50 mL), then dried (Na₂SO₄). After removal of solvent, thecrude product was purified by flash column chromatography on silica geleluting with hexane/ethyl acetate (1:1) to afford 119 mg (45%) of thetitle compound as white solids: ¹H-NMR (CDCl₃) δ 7.20 (2H, d, J=8.4 Hz),7.10 (2H, d, J=8.4 Hz), 7.01 (1H, d, J=2.3 Hz), 6.72 (1H, d, J=8.6 Hz),6.52 (1H, dd, J=2.3 Hz, 8.6 Hz), 3.45 (2H, t, J=7.4 Hz), 3.07 (2H, t,J=7.4 Hz), 2.56 (2H, q, J=7.5 Hz), 1.14 (3H, t, J=7.5 Hz), 0.79 (9H, s),0.05 (6H, s).

[1632] Step 3. 1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yltert-butyl(dimethyl)silyl ether

[1633] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-bromoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yltert-butyl(dimethyl)silyl ether (step 2).

[1634]¹H-NMR (CDCl₃) δ 7.20 (2H, d, J=8.3 Hz), 7.02-7.12 (3H, m), 6.70(1H, d, J=8.6 Hz), 6.50-6.54 (1H, m), 3.39 (2H, t, J=6.9 Hz), 2.79 (2H,t, J=6.9 Hz), 2.55 (2H, q, J=7.6 Hz), 1.13 (3H, t, J=7.6 Hz), 0.79 (9H,s), 0.00 (6H, s).

[1635] Step 4.2-[4-(5-{[tert-Butyl(dimethyl)silyl]oxy}-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1636] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yltert-butyl(dimethyl)silyl ether (step 3).

[1637]¹H-NMR (CDCl₃) δ 7.18 (2H, d, J=8.2 Hz), 7.02-7.08 (3H, m), 6.72(1H, d, J=8.6 Hz), 6.52 (1H, dd, J=2.2 Hz, 8.6 Hz), 2.86 (2H, t, J=6.6Hz), 2.66 (2H, t, J=6.6 Hz), 2.55 (2H, q, J=7.5 Hz), 1.13 (3H, t, J=7.5Hz), 0.79 (9H, s), 0.00 (6H, s).

[1638] Step 5.5-{[tert-Butyl(dimethyl)silyl]oxy}-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1639] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(5-{[tert-butyl(dimethyl)silyl]oxy}-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine(step 4).

[1640]¹H-NMR (CDCl₃) δ 7.53 (2H, d, J=8.3 Hz), 7.02-7.13 (7H, m), 6.70(1H, d, J=8.6 Hz), 6.52 (1H, dd, J=2.2 Hz, 8.6 Hz), 6.46 (1H, br.s),3.37 (2H, t, J=6.4 Hz), 2.71 (2H, t, J=6.4 Hz), 2.53 (2H, q, J=7.6 Hz),2.18 (3H, s), 1.11 (3H, t, J=7.6 Hz), 0.79 (9H, s), 0.00 (6H, s).

[1641] Step 6.2-Ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1642] A solution of5-{[tert-butyl(dimethyl)silyl]oxy}-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(step 5, 78 mg, 0.13 mmol) in THF (5 mL) was added tetrabutylammoniumfluoride (1.0 M solution in THF, 0.16 mL, 0.16 mmol) at 0° C. Themixture was stirred at 0° C. for 2.5 h, then concentrated. The residuewas dissolved in water (30 mL) and extracted with dichloromethane (50mL). The organic layer was dried (Na₂SO₄) and concentrated. The residuewas purified by flash column chromatography on silica gel eluting withdichloromethane/methanol (gradient elution from 20:1 to 10:1) to afford57 mg (92%) of the title compound as white amorphous: MS (ESI) m/z 479(M+H)⁺; ¹H-NMR (DMSO-d₆) δ 7.76 (2H, d, J=7.6 Hz), 7.35-7.39 (6H, m),6.96 (1H, s), 6.85 (1H, d, J=8.6 Hz), 6.65 (1H, d, J=8.6 Hz), 6.51 (1H,br.s), 3.17 (2H, br.s), 2.76 (2H, t, 6.6 Hz), 2.67 (2H, q, J=7.6 Hz),2.34 (3H, s), 1.20 (3H, t, J=7.6 Hz).

Example 912-Ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1643] Step 1. 2-[(3,4-Dimethyl-2-nitroanilino)phenyl]ethanol

[1644] The title compound was prepared according to the proceduredescribed in step 1 of Example 45 from 3,4-dimethyl-2-nitroaniline and4-bromophenylethyl ethanol.

[1645]¹H-NMR (CDCl₃) δ 7.16 (2H, d, J=8.4 Hz), 7.09 (1H, s), 7.03 (2H,d, J=8.4 Hz), 6.91 (1H, s), 3.89-3.81 (2H, m), 2.83 (2H, t, J=6.4 Hz),2.27 (3H, s), 2.25 (3H, s).

[1646] Step 2. 2-[(2-Amino-3,4-dimethylanilino)phenyl]ethanol

[1647] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[(3,4-dimethyl-2-nitroanilino)phenyl]ethanol (step 1).

[1648]¹H-NMR (CDCl₃) δ 7.02 (2H, d, J=8.6 Hz), 6.86 (1H, d, J=7.9 Hz),6.62-6.58 (3H, m), 5.09 (1H, br.s), 3.77 (2H, t, J=6.6 Hz), 2.74 (2H, t,J=6.6 Hz), 2.27 (3H, s), 2.11 (3H, s).

[1649] Step 3.2-[4-(2-Ethyl-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate

[1650] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[(2-amino-3,4-dimethylanilino)phenyl]ethanol (step 2) and propionylchloride.

[1651] MS (EI) m/z 350 (M⁺).

[1652] Step 4.2-[4-(2-Ethyl-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1653] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1654]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz),6.99 (1H, d, J=8.3 Hz), 6.82 (1H, d, J=8.3 Hz), 3.98 (2H, t, J=6.6 Hz),2.99 (2H, t, J=6.6 Hz), 2.82 (2H, q, J=7.5 Hz), 2.63 (3H, s), 2.39 (3H,s), 1.26 (3H, t, J=7.5 Hz).

[1655] Step 5.2-[4-(2-Ethyl-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide

[1656] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-[4-(2-ethyl-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1657]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz),7.00 (1H, d, J=8.2 Hz), 6.82 (1H, d, J=8.2 Hz), 3.61 (2H, t, J=7.1 Hz),3.01 (2H, t, J=7.1 Hz), 2.83 (2H, q, J=7.6 Hz), 2.63 (3H, s), 2.39 (3H,s), 1.26 (3H, t, J=7.6 Hz).

[1658] Step 6.2-[4-(2-Ethyl-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1659] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step5).

[1660]¹H-NMR (CDCl₃) δ 7.39 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz),6.99 (1H, d, J=8.2 Hz), 6.83 (1H, d, J=8.2 Hz), 3.09 (2H, t, J=6.6 Hz),2.92-2.79 (4H, m), 2.63 (3H, s), 2.39 (3H, s), 1.27 (3H, t, J=7.6 Hz).

[1661] Step 7.2-Ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1662] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step6).

[1663]¹H-NMR (CDCl₃) δ 7.76 (2H, d, J=8.2 Hz), 7.30-7.19 (6H, m), 7.00(1H, d, J=8.2 Hz), 6.81 (1H, d, J=8.2 Hz), 6.65 (1H, m), 3.56-3.54 (2H,m), 2.89 (2H, t, J=6.9 Hz), 2.80 (2H, q, J=7.6 Hz), 2.59 (3H, s), 2.38(6H, s), 1.22 (3H, t, J=7.6 Hz).

Example 922-Ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1664] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 91).

[1665]¹H-NMR (DMSO-d₆) δ 7.59 (2H, d, J=8.4 Hz), 7.39-7.30 (4H, m), 7.12(2H, d, J=8.4 Hz), 6.94 (1H, d, J=8.3 Hz), 6.77 (1H, d, J=8.3 Hz), 3.13(2H, m), 2.74-2.67 (4H, m), 2.48 (3H, s), 2.30 (3H, s), 2.27 (3H, s),1.19 (3H, t, J=7.5 Hz); IR (KBr) ν_(max) 1599, 1516, 1425, 1227, 1128,1086 cm⁻¹.

Example 934,6-Dimethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1666] Step 1. 2-[4-(3,5-Dimethyl-2-nitroanilino)phenyl]ethanol

[1667] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 4,6-dimethyl-2-fluoronitrobenzeneand 4-aminophenylethyl alcohol.

[1668]¹H-NMR (CDCl₃) δ 8.08 (1H, br.s), 7.22 (2H, d, J=8.4 Hz), 7.13(2H, d, J=8.4 Hz), 6.91 (1H, s), 6.51 (1H, s), 3.89 (2H, t, J=6.4 Hz),2.87 (2H, t, J=6.4 Hz), 2.47 (3H, s), 2.22 (3H, s).

[1669] Step 2. 2-[4-(2-Amino-3,5-dimethylanilino)phenyl]ethanol

[1670] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from2-[4-(3,5-dimethyl-2-nitroanilino)phenyl]ethanol (step 1).

[1671]¹H-NMR (CDCl₃) δ 6.97-7.04 (2H, m), 6.78 (1H, s), 6.74 (1H, s),6.59-6.67 (1H, s), 5.15 (1H, br.s), 3.76 (2H, t, J=6.6 Hz), 2.74 (2H, t,J=6.6 Hz), 2.18 (3H, s), 2.17 (3H, s).

[1672] Step 3.2-[4-(2-Ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate

[1673] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-3,5-dimethylanilino)phenyl]ethanol (step 2) and propionylchloride.

[1674] TLC Rf=0.7 (hexane/ethyl acetate=1:1).

[1675] Step 4.2-[4-(2-Ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1676] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-amino-3,5-dimethylanilino)phenyl]ethyl propionate (step 3).

[1677]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz),6.90 (1H, s), 6.71 (1H, s), 3.98 (2H, t, J=6.4 Hz), 2.99 (2H, t, J=6.4Hz), 2.81 (2H, q, J=7.3 Hz), 2.65 (3H, s), 2.36 (3H, s), 1.24 (3H, t,J=7.3 Hz).

[1678] Step 5.1-[4-(2-Chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole

[1679] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1680]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.0 Hz), 7.30 (2H, d, J=8.0 Hz),6.90 (1H, s), 6.71 (1H, s), 3.81 (2H, t, J=7.2 Hz), 3.19 (2H, t, J=7.2Hz), 2.81 (2H, q, J=7.7 Hz), 2.67 (3H, s), 2.37 (3H, s), 1.25 (3H, t,J=7.7 Hz).

[1681] Step 6.2-[4-(2-Ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide

[1682] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole (step5).

[1683]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz),6.90 (1H, s), 6.69 (1H, s), 3.62 (2H, t, J=7.0 Hz), 3.01 (2H, d, J=7.0Hz), 2.81 (2H, q, J=7.5 Hz), 2.66 (3H, s), 2.36 (3H, s), 1.25 (3H, t,J=7.5 Hz).

[1684] Step 7.2-[4-(2-Ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1685] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step6).

[1686]¹H-NMR (CDCl₃) δ 7.40 (2H, d, J=8.2 Hz), 7.27 (2H, d, J=8.2 Hz),6.89 (1H, s), 6.71 (1H, s), 3.07 (2H; t, J=6.9 Hz), 2.77-2.89 (4H, m),2.67 (3H, s), 2.36 (3H, s), 1.25 (3H, t, J=7.6 Hz).

[1687] Step 8.2-Ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1688] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step7).

[1689] mp 108-112° C.; MS (ESI) m/z 491 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.75(2H, d, J=8.2 Hz), 7.18-7.29 (6H, m), 6.89 (1H, s), 6.67 (1H, s), 6.62(1H, br.s), 3.51 (2H, br.s), 2.86 (2H, br.s), 2.76 (2H, q, J=7.4 Hz),2.63 (3H, s), 2.37 (3H, s), 2.33 (3H, s), 1.20 (3H, t, J=7.4 Hz).

Example 942-Ethyl-6-methyl-3-(4-{2-[({[(methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1690] Step 1. 2-[(4,5-Dimethyl-2-nitroanilino)phenyl]ethanol

[1691] The title compound was prepared according to the proceduredescribed in step 1 of Example 45 from 4,5-dimethyl-2-nitroaniline and4-bromophenylethyl alcohol.

[1692]¹H-NMR (CDCl₃) δ 9.39 (1H, br.s), 7.96 (1H, s), 7.27 (2H, d, J=8.4Hz), 7.21 (2H, d, J=8.4 Hz), 7.01 (1H, s), 3.91 (2H, q, H=6.4 Hz), 2.90(2H, t, J=6.4 Hz), 2.20 (3H, s), 2.19 (3H, s).

[1693] Step 2. 2-[(2-Amino-4,5-dimethylanilino)phenyl]ethanol

[1694] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[(4,5-dimethyl-2-nitroanilino)phenyl]ethanol (step 1).

[1695]¹H-NMR (CDCl₃) δ 7.04 (2H, d, J=8.4 Hz), 6.86 (1H, s), 6.64 (2H,d, J=8.4 Hz), 6.61 (1H, s), 3.79 (2H, t, J=6.6 Hz), 2.76 (2H, t, J=6.6Hz), 2.19 (3H, s), 2.12 (3H, s).

[1696] Step 3.2-[4-(2-Ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate

[1697] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[(2-amino-4,5-dimethylanilino)phenyl]ethanol (step 2) and propionylchloride.

[1698] MS (EI) m/z 350 (M⁺).

[1699] Step 4.2-[4-(2-Ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1700] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1701]¹H-NMR (CDCl₃) δ 7.52 (1H, s), 7.44 (2H, d, J=8.3 Hz), 7.28 (2H,d, J=8.3 Hz), 6.87 (1H, s), 4.00 (2H, t, J=6.6 Hz), 3.01 (2H, t, J=6.6Hz), 2.76 (2H, q, J=7.5 Hz), 2.36 (3H, s), 2.29 (3H, s), 1.31 (3H, t,J=7.5 Hz).

[1702] Step 5.2-[4-(2-Ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide

[1703] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-[4-(2-ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1704] TLC Rf=0.70 (hexane/ethyl acetate=1:1).

[1705] Step 6.2-[4-(2-Ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1706] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step5).

[1707]¹H-NMR (CDCl₃) δ 7.53 (1H, s), 7.40 (2H, d, J=8.1 Hz), 7.28 (2H,d, J=8.1 Hz), 6.87 (1H, s), 3.17 (2H, t, J=7.3 Hz), 3.00 (2H, t, J=7.3Hz), 2.76 (2H, q, J=7.5 Hz), 2.36 (3H, s), 2.29 (3H, s), 1.31 (3H, t,J=7.5 Hz).

[1708] Step 7.2-Ethyl-5,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1709] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step6).

[1710]¹H-NMR (CDCl₃) δ 7.79 (2H, d, J=8.1 Hz), 7.48 (1H, s), 7.29-7.15(6H, m), 6.86 (1H, s), 6.60 (1H, br.s), 3.57-3.55 (2H, m), 2.91-2.89(2H, m), 2.70 (2H, q, J=7.5 Hz), 2.39 (3H, s), 2.35 (3H, s), 2.27 (3H,s), 1.25 (3H, t, J=7.5 Hz).

Example 952-Ethyl-6-methyl-3-(4-{2-[({[(methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazolesodium salt

[1711] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-5,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 94).

[1712]¹H-NMR (DMSO-d₆) δ 7.60 (2H, d, J=8.1 Hz), 7.39-7.32 (5H, m), 7.13(2H, d, J=8.1 Hz), 6.86 (1H, s), 3.16 (2H, m), 2.73-2.64 (4H, m), 2.29(3H, s), 2.27 (3H, s), 2.23 (3H, s), 1.20 (3H, t, J=7.4 Hz); IR (KBr)ν_(max) 1599, 1516, 1468, 1404, 1283, 1236, 1130, 1086 cm⁻¹.

Example 965,6-Dichloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1713] Step 1. 2-[4-(4,5-Dichloro-2-nitroanilino)phenyl]ethanol

[1714] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,4,5-trichloronitrobenzene and4-aminophenylethyl alcohol.

[1715] MS (EI) m/z 327 (M⁺).

[1716] Step 2. 2-[4-(2-Amino-4,5-dichloroanilino)phenyl]ethanol

[1717] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[4-(4,5-dichloro-2-nitroanilino)phenyl]ethanol (step 1).

[1718]¹H-NMR (CDCl₃) δ 7.16 (1H, s), 7.11 (2H, d, J=8.0 Hz), 6.87 (1H,s), 6.74 (2H, d, J=8.0 Hz), 5.10 (1H, br.s), 3.90-3.60 (2H, m), 2.79(2H, t, J=7.0 Hz).

[1719] Step 3.2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate

[1720] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-4,5-dichloroanilino)phenyl]ethanol (step 2) and propionylchloride.

[1721] MS (EI) m/z 390 (M⁺); ¹H-NMR (CDCl₃) δ 7.84 (1H, s), 7.45 (2H, d,J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz), 7.16 (1H, s), 4.37 (2H, t, J=6.8 Hz),3.09 (2H, t, J=6.8 Hz), 2.77 (2H, q, J=7.5 Hz), 2.36 (2H, q, J=7.5 Hz),1.35 (3H, t, J=7.5 Hz), 1.16 (3H, t, J=7.5 Hz).

[1722] Step 4.2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1723] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate(step 3).

[1724]¹H-NMR (CDCl₃) δ 7.84 (1H, s), 7.47 (2H, d, J=8.0 Hz), 7.28 (2H,d, J=8.0 Hz), 7.18 (1H, s), 4.10-3.94 (2H, m), 3.01 (2H, t, J=6.4 Hz),2.77 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz).

[1725] Step 5.2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide

[1726] The title compound was prepared according to the proceduredescribed in step 5 Example 26 from2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).

[1727] MS (EI) m/z 359 (M⁺); ¹H-NMR (CDCl₃) δ 7.85 (1H, s), 7.46 (2H, d,J=8.1 Hz), 7.28 (2H, d, J=8.1 Hz), 7.17 (1H, s), 3.62 (2H, t, J=7.0 Hz),3.02 (2H, t, J=7.0 Hz), 2.76 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz).

[1728] Step 6.2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1729] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step5).

[1730]¹H-NMR (CDCl₃) δ 7.84 (1H, s), 7.43 (2H, d, J=8.4 Hz), 7.27 (2H,d, J=8.4 Hz), 7.22 (1H, s), 3.14 (2H, t, J=7.2 Hz), 2.97 (2H, t, J=7.2Hz), 2.76 (2H, q, J=7.6 Hz), 2.10 (2H, br.s), 1.34 (3H, t, J=7.6 Hz).

[1731] Step 7.5,6-Dichloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1732] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step6).

[1733]¹H-NMR (CDCl₃) δ 8.01 (1H, s), 7.70 (2H, d, J=8.3 Hz), 7.46 (2H,d, J=8.3 Hz), 7.36-7.29 (3H, m) 7.24 (2H, d, J=8.3 Hz), 6.81 (1H, br.s),3.57-3.46 (2H, m), 3.06-2.88 (4H, m), 2.38 (3H, s), 1.43 (3H, t, J=6.9Hz).

Example 97 2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[1734] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4of Example 96).

[1735]¹H-NMR (CDCl₃) δ 7.92 (2H, d, J=8.4 Hz), 7.85 (1H, s), 7.37 (2H,d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.16 (1H,s), 4.72 (1H, br.s), 4.38 (2H, t, J=6.8 Hz), 3.03 (2H, t, J=6.8 Hz),2.75 (2H, q, J=7.5 Hz), 2.44 (3H, s), 1.34 (3H, t, J=7.5 Hz).

Example 985,6-Dichloro-2-ethyl-1-(4-{2-[hydroxy({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1736] Step 1.1-[4-(2-{(tert-Butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino}ethyl)phenyl]-5,6-dichloro-2-ethyl-1H-benzimidazole

[1737] To a stirred mixture of2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (Example96, 100 mg, 0.3 mmol), N,O-Bis-tert-butoxycarbonylhydroxylamine(Baillie, L. C.; Batsanov, A.; Bearder, J. R.; Whiting, D. A. J. Chem.Soc. Perkin Trans. 1, 1998, 20, 3471., 140 mg, 0.6 mmol) andtriphenylphosphine (158 mg, 0.6 mmol) in THF (10 mL) was added diethylazodicarboxylate (DEAD) (0.1 mL, 0.6 mmol). The mixture was stirredunder nitrogen atmosphere at room temperature for 2.5 h. The solvent wasremoved and the residue was purified by flash column chromatography onsilica gel eluting with hexane/ethyl acetate (1:1) to afford 174 mg(quant.) of the title compound as yellow amorphous: ¹H-NMR (CDCl₃) δ7.84 (1H, s), 7.46 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.16 (1H,s), 3.92 (2H, t, J=6.7 Hz), 3.05 (2H, t, J=6.7 Hz), 2.76 (2H, q, J=7.6Hz), 1.56 (9H, s), 1.46 (9H, s), 1.33 (3H, t, J=7.6 Hz).

[1738] Step 2.N-{2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl}hydroxylamine

[1739] A mixture of1-[4-(2-{(tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino}ethyl)phenyl]-5,6-dichloro-2-ethyl-1H-benzimidazole(step 1, 174 mg, 0.3 mmol) and 2N hydrochloric acid (3 mL) in ethylacetate (20 mL) was stirred at room temperature for 1 day. The reactionmixture was poured into water (100 mL), neutralized with saturatedaqueous sodium bicarbonate, and extracted with ethyl acetate (100 mL).The organic layer was washed with brine (50 mL), dried (Na₂SO₄), andconcentrated to afford 162 mg (quant.) of the title compound as a yellowoil: ¹H-NMR (CDCl₃) δ 10.35 (2H, br.s), 7.89 (1H, s), 7.46-7.50 (2H, m),7.29 (2H, d, J=6.8 Hz), 7.17 (1H, s), 3.37 (2H, t, J=6.9 Hz), 3.12 (2H,t, J=6.9 Hz), 2.80 (2H, q, J=6.9 Hz), 1.34 (3H, m).

[1740] Step 3.5,6-Dichloro-2-ethyl-1-(4-{2-[hydroxy({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1741] The reaction was carried out according to the procedure describedin step 10 of Example 1 fromN-{2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl}hydroxylamine(step 2).

[1742] MS (ESI) m/z 547 (M+H)⁺; ¹H-NMR (CDCl₃) δ: 7.92 (2H, d, J=8.4Hz), 7.79 (2H, d, J=7.2 Hz), 7.34-7.45 (2H, m), 7.13-7.18 (4H, m), 3.85(1H, br.s), 3.05 (2H, br.s), 2.66-2.80 (4H, m), 2.38 (3H, s), 1.32 (3H,t, J=7.4 Hz); IR (KBr) ν_(max) 1654, 1517, 1452, 1164, 1095, 869 cm⁻¹.

Example 995,6-Dichloro-2-ethyl-1-(4-{cis-3-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]cyclobutyl}phenyl)-1H-benzimidazole

[1743] Step 1. trans-3-Phenylcyclobutyl benzoate

[1744] To a stirred solution of cis-3-phenylcyclobutanol (Eckehard, V.D.; et al. Chem. Ber., 1993, 126, 2759., 4.6 g, 30.2 mmol),triphenylphosphine (3.3 g, 59.1 mmol) and benzoic acid (7.6 mg, 62.3mmol) was added diethyl azodicarboxylate (DEAD) (10.9 g, 62.3 mmol) atroom temperature. The resulting mixture was stirred at room temperaturefor 40 min, then the mixture was concentrated. The residue was dissolvedin diethyl ether (100 mL) and washed with saturated aqueous sodiumbicarbonate (50 mL), water (50 mL), and brine (50 mL). The organic layerwas dried (Na₂SO₄), and concentrated. Purification by flash columnchromatography on silica gel eluting with hexane/ethyl acetate (10:1) toafford 6.52 g (86%) of the title compound as a pale yellow oil: ¹H-NMR(CDCl₃) δ 7.71-7.20 (10H, m), 5.49-5.41 (1H, m), 3.82-3.72 (1H, m),2.78-2.64 (4H, m).

[1745] Step 2. trans-3-Phenylcyclobutanol

[1746] To a solution of trans-3-phenylcyclobutyl benzoate (step 1, 6.5g, 26.0 mmol) in methanol (100 mL) was added 4N aqueous LiOH (20 mL, 80mmol) and the resulting mixture was stirred at room temperature for 10min. The mixture was concentrated. The residue was dissolved in water(100 mL) and extracted with ethyl acetate (100 mL). The organic layerwas washed with brine (100 mL), dried (Na₂SO₄), and concentrated.Purification by flash column chromatography on silica gel eluting withhexane/ethyl acetate (5:1) to afford 3.65 g (93%) of the title compoundas a colorless oil: ¹H-NMR (CDCl₃) δ 7.34-7.16 (5H, m), 4.60-4.51 (1H,m), 3.69-3.59 (1H, m), 2.55-2.37 (4H, m).

[1747] Step 3. trans-3-(4-Nitrophenyl)cyclobutanol

[1748] To a mixture of nitric acid (fuming, 2.3 mL) and acetic anhydride(25 mL) was added dropwise a mixture of trans-3-phenylcyclobutylbenzoate (step 2, 3.7 g, 24.6 mmol) and sulfuric acid in aceticanhydride (25 mL) at −23° C. The resulting mixture was stirred in anice-bath for 1.5 h. The mixture was poured into ice water (200 mL) andextracted with dichloromethane (2×100 mL). The organic layer was washedwith water and brine (100 mL), then dried (Na₂SO₄), and concentrated.The oily residue was dissolved in methanol (100 mL), and 4N aqueous LiOH(50 mL) was added. The resulting mixture was stirred at room temperaturefor 10 min, then concentrated. The residue was dissolved in water (100mL) and extracted with ethyl acetate (100 mL). The organic layer waswashed with brine, dried (Na₂SO₄), and concentrated. Purification byflash column chromatography on silica gel eluting with hexane/ethylacetate (2:1) to afford 2.7 g (56%) of the title compound as a paleyellow oil: MS (EI) m/z 193 (M⁺); ¹H-NMR (CDCl₃) δ 8.18 (2H, d, J=8.6Hz), 7.38 (2H, d, J=8.6 Hz), 4.62-4.52 (1H, m), 3.81-3.71 (1H, m),2.54-2.45 (4H, m).

[1749] Step 4. trans-3-(4-Aminophenyl)cyclobutanol

[1750] To a stirred solution of trans-3-(4-nitrophenyl)cyclobutanol(step 3, 1.0 g, 4.9 mmol) in methanol (20 mL) was added 10% Pd—C (50mg). The mixture was stirred at room temperature under hydrogenatmosphere for 2.5 h. The palladium catalyst was removed by filtrationand washed with methanol (100 mL) and ethyl acetate (100 mL). Thefiltrate was concentrated under reduced pressure to afford 0.9 g(quant.) of the title compound as pale yellow solids: MS (EI) m/z 163(M⁺); ¹H-NMR (CDCl₃) δ 7.03 (2H, d, J=8.3 Hz), 6.66 (2H, d, J=8.3 Hz),4.56-4.47 (1H, m), 3.58-3.48 (3H, m), 2.48-2.31 (2H, m), 1.73 (1H, d,J=5.1 Hz).

[1751] Step 5.trans-3-[4-(4,5-Dichloro-2-nitroanilino)phenyl]cyclobutanol

[1752] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,4,5-trichloronitrobenzene andtrans-3-(4-aminophenyl)cyclobutanol (step 4).

[1753]¹H-NMR (CDCl₃) δ 9.40 (1H, br.s), 8.27 (1H, s), 7.33 (2H, d, J=8.1Hz), 7.22 (2H, d, J=8.1 Hz), 7.19 (1H, s), 4.63-4.55 (1H, m), 3.73-3.63(1H, m), 2.57-2.43 (4H, m).

[1754] MS (EI) m/z: 352 (M⁺).

[1755] Step 6.trans-3-[4-(2-Amino-4,5-dichloroanilino)phenyl]cyclobutanol

[1756] The title compound was prepared according to the proceduredescribed in step 3 of Example 6 fromtrans-3-[4-(4,5-dichloro-2-nitroanilino)phenyl]cyclobutanol (step 5).

[1757]¹H-NMR (CDCl₃) δ 7.16 (1H, s), 7.12 (2H, d, J=8.6 Hz), 6.86 (1H,s), 6.75 (2H, d, J=8.6 Hz), 5.08 (1H, br.s), 4.58-4.49 (1H, m), 3.77(2H, br.s), 3.62-3.52 (1H, m), 2.50-2.34 (4H, m).

[1758] Step 7.trans-3-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]cyclobutylpropionate

[1759] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 fromtrans-3-[4-(2-amino-4,5-dichloroanilino)phenyl]cyclobutanol (step 6) andpropionyl chloride.

[1760] TLC Rf=0.56 (ethyl acetate/hexane=1:1).

[1761] Step 8.trans-3-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]cyclobutanol

[1762] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 fromtrans-3-[4-(2-amino-4,5-dichloroanilino)phenyl]cyclobutyl propionate(step 7).

[1763] MS (EI) m/z: 360 (M⁺); ¹H-NMR (CDCl₃) δ 7.85 (1H, br.s), 7.45(2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz), 7.18 (1H, br.s), 4.65-4.55(1H, m), 3.83-3.73 (1H, m), 2.77 (2H, q, J=7.5 Hz), 2.63-2.48 (4H, m),1.34 (3H, t, J=7.5 Hz).

[1764] Step 9.cis-3-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]cyclobutylazide

[1765] To a stirred solution oftrans-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]cyclobutanol(step 8, 572 mg, 1.6 mmol), triphenylphosphine (623 mg, 2.4 mmol) anddiphenylphosphoryl azide (DPPA) (655 mg, 2.4 mmol) in THF (8 mL) wasadded diethyl azodicarboxylate (415 mg, 2.4 mmol) at room temperature.The resulting mixture was stirred at room temperature for 3 h, then themixture was diluted with ethyl acetate (100 mL) and washed with water(100 mL) and brine (100 mL). The organic layer was dried (Na₂SO₄), andconcentrated. Purification by flash column chromatography on silica geleluting with hexane/ethyl acetate (2:1) to afford 506 mg (83%) of thetitle compound as colorless solids: MS (EI) m/z: 385 (M⁺); ¹H-NMR(CDCl₃) δ 7.84 (1H, br.s), 7.42 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3Hz), 7.17 (1H, br.s), 3.98-3.88 (1H, m), 3.37-3.25 (1H, m), 2.89-2.75(2H, m), 2.77 (2H, q, J=7.6 Hz), 2.34-2.23 (2H, m), 1.34 (3H, t, J=7.6Hz).

[1766] Step 10.cis-3-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]cyclobutylamine

[1767] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 fromcis-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]cyclobutylazide (step 9).

[1768] MS (EI) m/z 359 (M⁺); ¹H-NMR (CDCl₃) δ 7.84 (1H, br.s), 7.41 (2H,d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.17 (1H, br.s), 3.55-3.43 (1H,m), 3.24-3.12 (1H, m), 2.87-2.73 (4H, m), 1.91-1.80 (2H, m), 1.34 (3H,t, J=7.5 Hz).

[1769] Step 11.5,6-Dichloro-2-ethyl-1-(4-{cis-3-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]cyclobutyl}phenyl)-1H-benzimidazole

[1770] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 fromcis-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]cyclobutylamine(step 10).

[1771] MS (ESI) m/z 557 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.85 (1H, br.s), 7.79(2H, d, J=8.4 Hz), 7.42 (2H, d, J=8.1 Hz), 7.36 (2H, d, J=8.1 Hz), 7.28(2H, d, J=8.4 Hz), 7.17 (1H, br.s), 4.35-4.26 (1H, m), 3.35-3.25 (1H,m), 2.93-2.83 (2H, m), 2.78 (2H, q, J=7.6 Hz), 2.46 (3H, s), 2.19-2.07(2H, m), 1.34 (3H, t, J=7.6 Hz).

Example 1005,6-Dichloro-1-(4-{1,1-dimethyl-2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-1H-benzimidazole

[1772] Step 1.2-[4-(4,5-Dichloro-2-nitroanilino)phenyl]-2-methylpropanenitrile

[1773] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,4,5-trichloronitroaniline and2-(4-aminophenyl)-2-methylpropanenitrile (Axton, C. A.; et al.J.Chem.Soc.Perkin Trans.1, 1992, 17, 2203).

[1774]¹H-NMR (CDCl₃) δ 9.38 (1H, br), 8.31 (1H, s), 7.54 (2H, d, J=8.58Hz), 7.30-7.22 (3H, m), 1.75 (6H, s).

[1775] Step 2.2-[4-(2-Amino-4,5-dichloroanilino)phenyl]-2-methylpropanenitrile

[1776] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[4-(4,5-dichloro-2-nitroanilino)phenyl]-2-methylpropanenitrile (step1).

[1777]¹H-NMR (CDCl₃) δ 7.41 (1H, s), 7.30 (2H, d, J=8.4 Hz), 7.09 (1H,s), 6.90 (1H, s), 6.80 (2H, d, J=8.4 Hz), 5.22 (2H, s), 1.62 (6H, s).

[1778] Step 3.2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]-2-methylpropanenitrile

[1779] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-4,5-dichloroanilino)phenyl]-2-methylpropanenitrile (step2) and propionyl chloride.

[1780]¹H-NMR (CDCl₃) δ 7.91 (1H, s), 7.78 (2H, d, J=8.4 Hz), 7.45 (2H,d, J=8.4 Hz), 7.24 (1H, s), 2.83 (2H, q, J=7.5 Hz), 1.89 (6H, s), 1.42(3H, t, J=7.3 Hz).

[1781] Step 4.5,6-Dichloro-1-(4-{1,1-dimethyl-2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-1H-benzimidazole

[1782] A mixture of2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]-2-methylpropanenitrile(step 3, 102 mg, 0.28 mmol), PtO₂ (one portion), chloroform (0.5 mL) inethanol (15 mL) was stirred under hydrogen atmosphere (4.5 Kg/cm²) atroom temperature. After 8 h, the mixture was filtered through a pad ofCelite, and the filtrate was concentrated. The residue was suspended indichloromethane (10 mL). To the suspension was added p-toluenesulfonylisocyanate (0.3 mL, 1.96 mmol), and triethylamine (0.3 mL, 2.1 mmol) atroom temperature. After 0.5 h, the mixture was concentrated. The residuewas dissolved in dichloromethane (100 mL) and washed with 10% aqueouscitric acid (50 mL), water (50 mL), and brine (50 mL). The organic layerwas dried (MgSO₄) and concentrated. The residue was purified bypreparative TLC (ethyl acetate/hexane=2:1) to give 62 mg (37%) of thetitle compound as white solids: ¹H-NMR (CDCl₃) δ 7.83 (1H, s), 7.67 (2H,d, J=9.3 Hz), 7.55 (2H, d, J=9.3 Hz), 7.38-7.22 (4H, m), 7.18 (1H, s),3.45 (1H, br), 2.76 (2H, q, J=8.4 Hz), 2.34 (3H, s), 1.37 (6H, s), 1.31(3H, t, J=8.2 Hz).

Example 101

[1783] Step 1. Ethyl [4-(4,5-dichloro-2-nitroanilino)phenyl]acetate

[1784] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from ethyl 2,4,5-trichloronitrobenzeneand 4-aminophenylacetate.

[1785]¹H-NMR (CDCl₃) δ 9.41 (1H, s), 8.32 (1H, s), 7.37 (2H, d, J=8.4Hz), 7.28 (1H, s), 7.22 (2H, d, J=8.3 Hz), 4.19 (2H, q, J=7.1 Hz), 3.66(2H, s), 1.29 (3H, t, J=7.1 Hz).

[1786] Step 2. Ethyl [4-(2-amino-4,5-dichloroanilino)phenyl]acetate

[1787] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from ethyl[4-(4,5-dichloro-2-nitroanilino)phenyl]acetate (step 1).

[1788]¹H-NMR (CDCl₃) δ 7.16 (1H, s), 7.15 (2H, d, J=7.5 Hz), 6.86 (1H,s), 6.72 (2H, d, J=7.1 Hz), 5.12 (1H, br.s), 4.15 (2H, q, J=7.0 Hz),3.79 (2H, br), 3.54 (2H, s), 1.26 (3H, t, J=7.1 Hz).

[1789] Step 3. Ethyl[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetate

[1790] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from ethyl[4-(2-amino-4,5-dichloroanilino)phenyl]acetate (step 2) and propionylchloride.

[1791]¹H-NMR (CDCl₃) δ 7.84 (1H, s), 7.52 (2H, d, J=8.2 Hz), 7.30 (2H,d, J=8.4 Hz), 7.19 (1H, s), 4.22 (2H, q, J=7.1 Hz), 3.75 (2H, s), 2.77(2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz), 1.32 (3H, t, J=7.1 Hz).

[1792] Step 4.[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetic acid

[1793] To a stirred solution of ethyl[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetate (step 3,1.30 g, 3.4 mmol) in methanol was added 2N aqueous NaOH (3.4 mL) at roomtemperature. After 1 h, the mixture was concentrated and the residue wasdiluted in water (200 mL) and the mixture was washed with diethyl ether(100 mL). The aqueous layer was acidified with 2N hydrochloric acid andextracted with ethyl acetate/THF (v/v, 1:1, 300 mL). The organic extractwas washed with water (200 mL), brine (200 mL), and dried (MgSO₄).Removal of solvent gave 1.02 g (86%) of the title compound as a whitepowder: ¹H-NMR (CDCl₃) δ 7.94 (1H, s), 7.56-7.45 (4H, m), 7.26 (1H, s),3.72 (2H, s), 2.72 (2H, q, J=7.3 Hz), 1.22 (3H, t, J=7.5 Hz).

[1794] Step 5.2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetamide

[1795] A mixture of[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetic acid (step4, 0.81 g, 2.3 mmol) and thionyl chloride (10 mL) was stirred for 0.5 h,and concentrated. To the residue was added ammonium hydroxide (28% NH₃in water, 50 mL) and the mixture was extracted with ethyl acetate/THF(v/v, 1:1, 200 mL). The extract was washed with brine (2×100 mL), dried(MgSO₄), and concentrated. The residue was purified by flash columnchromatography on silica gel eluting with dichloromethane/methanol(20:1) to give 349 mg (44%) of the title compound as yellow solids:¹H-NMR (CDCl₃) δ 7.93 (1H, s), 7.58 (1H, br), 7.51 (2H, d, J=8.4 Hz),7.47 (2H, d, J=8.4 Hz), 7.27 (1H, s), 7.00 (1H, br), 3.51 (2H, s), 2.71(2H, q, J=7.5 Hz), 1.21 (3H, t, J=7.5 Hz).

[1796] Step 6.2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]-N-({[(4-methylphenyl)sulfonyl]amino}carbonyl)acetamide

[1797] A mixture of2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetamide (step5, 105 mg, 0.30 mmol), p-toluenesulfonyl isocyanate (0.07 mL, 0.45mmol), toluene (10 mL) and THF (5 mL) was heated at reflux temperature.After 6 h, an additional 0.1 mL of p-toluenesulfonyl isocyanate wasadded and the mixture was heated for 3 h. The mixture was cooled andleft at room temperature for 2 days. The mixture was concentrated andthe residue was purified by preparative TLC (ethyl acetate) to afford150 mg (92%) of the title compound as colorless amorphous solids: ¹H-NMR(CDCl₃) δ 9.78 (1H, s), 7.95 (2H, d, J=8.3 Hz), 7.84 (1H, s), 7.54 (2H,d, J=8.4 Hz), 7.34 (2H, d, J=8.0 Hz), 7.32 (2H, d, J=8.4 Hz), 7.18 (1H,s), 3.78 (2H, s), 2.77 (2H, q, J=7.5 Hz), 2.41 (3H, s), 1.35 (3H, t,J=7.5 Hz).

Example 1025,6-Dichloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1798] Step 1. 2-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)phenyl]ethylformate

[1799] A mixture of 2-[(4,5-dichloro-2-anilino)phenyl]ethanol (450 mg,1.42 mmol) and formic acid (7 mL) was stirred at reflux for 4 h. Aftercooling, the mixture was made basic with 2N aqueous NaOH and extractedwith ethyl acetate (50 mL). The extracts was dried (MgSO₄) to afford 480mg (quant.) of the title compound as a brown oil: ¹H-NMR (CDCl₃) δ 8.10(1H, s), 8.08 (1H, s), 7.95 (1H, s), 7.61 (1H, s), 7.49-7.41 (4H, m),4.47 (2H, t, J=6.8 Hz), 3.10 (2H, t, J=6.8 Hz).

[1800] Step 2. 2-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)phenyl]ethanol

[1801] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5,6-dichloro-1H-benzimidazol-1-yl)phenyl]ethyl formate (step 1).

[1802]¹H-NMR (CDCl₃) δ 8.08 (1H, s), 7.96 (1H, s), 7.61 (1H, s),7.49-7.40 (4H, m), 3.97 (2H, q, J=6.4 Hz), 2.99 (2H, t, J=6.4 Hz).

[1803] Step 3. 2-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)phenyl]ethylazide

[1804] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-[4-(5,6-dichloro-1H-benzimidazol-1-yl)phenyl]ethanol (step 2).

[1805] MS (EI) m/z 332 (M⁺).

[1806] Step 4. 2-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)phenyl]ethylamine

[1807] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(5,6-dichloro-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 3).

[1808]¹H-NMR (CDCl₃) δ 8.09 (1H, s), 7.96 (1H, s), 7.62 (1H, s),7.45-7.38 (4H, m), 3.06 (2H, m), 2.87 (2H, t, J=6.6 Hz).

[1809] Step 5.5,6-Dichloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1810] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(5,6-dichloro-1H-benzimidazol-1-yl)phenyl]ethylamine (step 3).

[1811]¹H-NMR (CDCl₃) δ 8.11 (1H, s), 7.96 (1H, s), 7.72 (2H, d, J=8.4Hz), 7.58 (1H, s), 7.38 (4H, s), 7.28 (2H, d, J=8.4 Hz), 6.72 (1H, m),3.56 (2H, q, J=6.9 Hz), 2.92 (2H, t, J=6.9 Hz), 2.38 (3H, s).

Example 1035,6-Dichloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1812] The title compound was prepared according to the proceduredescribed in Example 2 from5,6-dichloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 102).

[1813]¹H-NMR (DMSO-d₆) δ 8.55 (1H, s), 7.97 (1H, s), 7.71 (1H, s),7.50-7.44 (4H, m), 7.29 (2H, d, J=8.4 Hz), 7.01 (2H, d, J=8.4 Hz), 3.02(2H, m), 2.61 (2H, m), 2.16 (3H, s); IR (KBr) ν_(max) 1601, 1516, 1487,1450, 1128, 1084 cm⁻¹.

Example 1046-Chloro-5-trifluoromethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1814] Step 1.2-[(5-Chloro-4-trifluoromethyl-2-nitroanilino)phenyl]ethanol

[1815] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from2,4-dichloro-5-trifluoromethylnitrobenzene and 4-aminophenylethylalcohol.

[1816]¹H-NMR (CDCl₃) δ 9.69 (1H, br.s), 8.58 (1H, s), 7.37 (2H, d, J=8.4Hz), 7.23 (2H, d, J=8.4 Hz), 7.19 (1H, s), 3.93 (2H, t, J=6.4 Hz), 2.94(2H, t, J=6.4 Hz).

[1817] Step 2.2-[(2-Amino-5-chloro-4-trifluoromethylanilino)phenyl]ethanol

[1818] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[(5-chloro-4-trifluoromethyl-2-nitroanilino)phenyl]ethanol (step 1).

[1819]¹H-NMR (CDCl₃) δ 7.17-7.15 (3H, m), 7.05 (1H, s), 6.92-6.88 (2H,m), 5.48 (1H, br.s), 3.85 (2H, t, J=6.6 Hz), 2.83 (2H, t, J=6.6 Hz).

[1820] Step 3.2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1821] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[(2-amino-5-chloro-4-trifluoromethylanilino)phenyl]ethanol (step 2)and propionyl chloride.

[1822] MS (El) 424 (M⁺).

[1823] Step 4.2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1824] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate (step 3).

[1825]¹H-NMR (CDCl₃) δ 8.11 (1H, s), 7.50 (2H, d, J=8.3 Hz), 7.29 (2H,d, J=8.3 Hz), 7.21 (1H, s), 4.03-3.98 (2H, m), 3.02 (2H, t, J=6.4 Hz),2.79 (2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz).

[1826] Step 52-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethylazide

[1827] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethanol(step 4).

[1828]¹H-NMR (CDCl₃) δ 8.11 (1H, s), 7.49 (2H, d, J=8.4 Hz), 7.30 (2H,d, J=8.4 Hz), 7.20 (1H, s), 3.63 (2H, t, J=6.9 Hz), 3.03 (2H, t, J=6.9Hz), 2.79 (2H, q, J=7.4 Hz), 1.36 (3H, t, J=7.4 Hz).

[1829] Step 6.2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1830] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethylazide (step 5).

[1831]¹H-NMR (CDCl₃) δ 8.11 (1H, s), 7.45 (2H, d, J=8.3 Hz), 7.29-7.26(2H, m), 7.23 (1H, s), 3.11 (2H, t, J=7.0 Hz), 2.92 (2H, t, J=7.0 Hz),2.79 (2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz).

[1832] Step 72-Ethyl-6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1833] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethylamine(step 6).

[1834]¹H-NMR (CDCl₃) δ 8.09 (1H, s), 7.74 (2H, d, J=8.4 Hz), 7.42 (2H,d, J=8.2 Hz), 7.30-7.26 (4H, m), 7.18 (1H, s), 6.76 (1H, m), 3.59 (2H,q, J=7.0 Hz), 2.96 (2H, t, J=7.0 Hz), 2.79 (2H, q, J=7.6 Hz), 1.34 (3H,t, J=7.6 Hz).

Example 1056-Chloro-5-trifluoromethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1835] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 104).

[1836]¹H-NMR (DMSO-d₆) δ 8.15 (1H, s), 7.59 (2H, d, J=8.4 Hz), 7.46-7.39(4H, m), 7.33 (1H, s), 7.12 (2H, d, J=8.4 Hz), 3.15 (2H, m), 2.78-2.71(4H, m), 1.24 (3H, t, J=7.5 Hz); IR (KBr) ν_(max) 1.601, 1518, 1431,1398, 1348, 1306, 1128, 1084 cm⁻¹.

Example 1064-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamate

[1837] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethanol(step 4 of Example 104).

[1838] mp 170-173° C.; ¹H-NMR (CDCl₃) δ 8.12 (1H, s), 7.94-7.91 (2H, m),7.41-7.24 (6H, m), 7.19 (1H, s), 4.39 (2H, t, J6.8 Hz), 3.04 (2H, t,J=6.8 Hz), 2.78 (2H, q, J=7.6 Hz), 2.44 (3H, s), 1.35 (3H, t, J=7.6 Hz);IR (KBr) ν_(max) 1746, 1518, 1342, 1232, 1159, 1132, 1086 cm⁻¹.

Example 1074-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamate,sodium salt

[1839] The title compound was prepared according to the proceduredescribed in Example 2 from4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamate(Example 106).

[1840]¹H-NMR (DMSO-d₆) δ 8.15 (1H, s), 7.59 (2H, d, J=8.1 Hz), 7.47 (4H,s), 7.34 (1H, s), 7.15 (2H, d, J=8.1 Hz), 3.96 (2H, t, J=6.6 Hz), 2.86(2H, t, J=6.6 Hz), 2.75 (2H, q, J=7.4 Hz), 2.28 (3H, s), 1.24 (3H, t,J=7.4 Hz).

Example 1085-Chloro-6-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1841] Step 1. 2-[(4-Chloro-5-methyl-2-nitroanilino)phenyl]ethanol

[1842] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,5-dichloro-4-methylnitrobenzeneand 4-aminophenylethyl alcohol.

[1843]¹H-NMR (CDCl₃) δ 9.40 (1H, s), 8.20 (1H, s), 7.31 (2H, d, J=8.4Hz), 7.21 (2H, d, J=8.4 Hz), 7.05 (1H, s), 3.93-3.91 (2H, m), 2.91 (2H,t, J=6.4 Hz), 2.29 (3H, s)

[1844] Step 2. 2-[(2-Amino-4-chloro-5-methylanilino)phenyl]ethanol

[1845] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[(4-chloro-5-methyl-2-nitroanilino)phenyl]ethanol (step 1).

[1846]¹H-NMR (CDCl₃) δ 7.06 (2H, d, J=8.6 Hz), 6.93 (1H, s), 6.79 (1H,s), 6.67 (2H, d, J=8.6 Hz), 3.80 (2H, d, J=6.4 Hz), 2.77 (2H, t, J=6.4Hz), 2.21 (3H, s).

[1847] Step 3.2-[4-(5-Chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1848] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[(2-amino-4-chloro-5-methylanilino)phenyl]ethanol (step 2) andpropionyl chloride.

[1849] MS (El) m/z 370 (M⁺).

[1850] Step 4.2-[4-(5-Chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethanol

[1851] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5-chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate (step 3).

[1852]¹H-NMR (CDCl₃) δ 7.74 (1H, s), 7.47 (2H, d, J=8.3 Hz), 7.27 (2H,d, J=8.3 Hz), 6.93 (1H, s), 4.00 (2H, t, J=6.6 Hz), 3.02 (2H, t, J=6.6Hz), 2.76 (2H, q, J=7.5 Hz), 2.39 (3H, s), 1.32 (3H, t, J=7.5 Hz).

[1853] Step 5.2-[4-(5-Chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide

[1854] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-[4-(5-chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethanol(step 4).

[1855]¹H-NMR (CDCl₃) δ 7.75 (1H, s), 7.45 (2H, d, J=8.4 Hz), 7.30 (2H,d, J=8.4 Hz), 7.27 (1H, s), 3.62 (2H, t, J=7.0 Hz), 3.02 (2H, t, J=7.0Hz), 2.76 (2H, q, J=7.5 Hz), 2.40 (3H, s), 1.33 (3H, t, J=7.5 Hz).

[1856] Step 6.2-[4-(5-Chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine

[1857] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(5-chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide(step 5).

[1858]¹H-NMR (CDCl₃) δ 7.75 (1H, s), 7.42 (2H, d, J=8.3 Hz), 7.27 (2H,d, J=8.3 Hz), 6.93 (1H, s), 3.10 (2H, t, J=7.0 Hz), 2.90 (2H, t, J=7.0Hz), 2.76 (2H, q, J=7.5 Hz), 2.40 (3H, s), 1.33 (3H, t, J=7.5 Hz).

[1859] Step 7.2-Ethyl-5-chloro-6-methyl-1-(4-{2-[([[(4-methylphenyl)sulfonyl]amino]carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[1860] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(5-chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylamine(step 6).

[1861]¹H-NMR (CDCl₃) δ 7.75-7.72 (3H, m), 7.38-7.23 (6H, m), 6.91 (1H,s), 6.73-6.69 (1H, m), 3.62-3.55 (2H, m), 2.94 (2H, t, J=6.8 Hz), 2.75(2H, q, J=7.6 Hz), 2.40 (3H, s), 2.37 (3H, s), 1.30 (3H, t, J=7.6 Hz).

Example 1095-Chloro-6-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole,sodium salt

[1862] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-5-chloro-6-methyl-1-(4-{2-[([[(4-methylphenyl)sulfonyl]amino]carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(Example 108).

[1863]¹H-NMR (DMSO-d₆) δ 7.68 (1H, s), 7.60 (2H, d, J=8.1 Hz), 7.41-7.35(4H, m), 7.13 (2H, d, J=8.1 Hz), 7.05 (1H, s), 3.17-3.15 (2H, m),2.75-2.65 (4H, m), 2.34 (3H, s), 2.27 (3H, s), 1.20 (3H, t, J=7.5 Hz);IR (KBr) ν_(max) 1599, 1516, 1456, 1402, 1128, 1084, 1001 cm⁻¹.

Example 1106-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-[(methylsulfonyl)amino]-1H-benzimidazole

[1864] Step 1. 2-[4-(5-Chloro-2,4-dinitroanilino)phenyl]ethanol

[1865] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,4-dichloro-1,5-dinitrobenzeneand 4-aminophenylethyl alcohol.

[1866]¹H-NMR (CDCl₃) δ 9.81 (1H, br.s), 9.07 (1H, s), 7.40 (2H, d, J=8.3Hz), 7.25 (2H, d, J=8.3 Hz), 7.17 (1H, s), 3.95 (2H, t, J=6.6 Hz), 2.95(2H, t, J=6.6 Hz).

[1867] Step 2. 2-[4-(2-Amino-5-chloro-4-nitroanilino)phenyl]ethanol

[1868] The title compound was prepared according to the proceduredescribed in step 2 of Example 40 from2-[4-(5-chloro-2,4-dinitroanilino)phenyl]ethanol (step 1).

[1869]¹H-NMR (CDCl₃) δ 7.54 (1H, s), 7.24 (2H, d, J=8.6 Hz), 7.11 (1H,s), 7.03 (2H, d, J=8.6 Hz), 5.76 (1H, br.s), 3.89 (2H, t, J=6.4 Hz),3.65 (2H, br.s), 2.87 (2H, t, J=6.4 Hz), 1.28 (1H, s).

[1870] Step 3.2-[4-(6-Chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1871] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-(2-amino-5-chloro-4-nitroanilino)phenyl]ethanol (step 2) andpropionyl chloride.

[1872] TLC Rf=0.8 (hexane/ethyl acetate=1:2).

[1873] Step 4.2-[4-(6-Chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]ethanol

[1874] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-amino-5-chloro-4-nitroanilino)phenyl]ethyl propionate (step 3).

[1875]¹H-NMR (CDCl₃) δ 8.34 (1H, s), 7.50 (2H, d, J=8.0 Hz), 7.28 (2H,d, J=8.0 Hz), 7.19 (1H, s), 4.00 (2H, t, J=6.3 Hz), 3.02 (2H, t, J=6.3Hz), 2.79 (2H, q, J=7.6 Hz), 1.62 (1H, s), 1.36 (3H, t, J=7.6 Hz).

[1876] Step 5.6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-nitro-1H-benzimidazole

[1877] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(6-chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]ethanol (step4).

[1878]¹H-NMR (CDCl₃) δ 8.34 (1H, s), 7.50 (2H, d, J=8.4 Hz), 7.31 (2H,d, J=8.4 Hz), 7.19 (1H, s), 3.84 (2H, t, J=7.0 Hz), 3.22 (2H, t, J=7.0Hz), 2.80 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).

[1879] Step 6.6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine

[1880] The title compound was prepared according to the proceduredescribed in step 4 of Example 89 from6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-nitro-1H-benzimidazole(step 5).

[1881]¹H-NMR (CDCl₃) δ 7.43 (2H, d, J=8.6 Hz), 7.29 (2H, d, J=8.6 Hz),7.16 (1H, s), 7.02 (1H, s), 3.96 (2H, br.s), 3.81 (2H, t, J=7.1 Hz),3.19 (2H, t, J=7.1 Hz), 2.74 (2H, q, J=7.5 Hz), 1.33 (3H, t, J=7.5 Hz).

[1882] Step 7.N-{6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide

[1883] The title compound was prepared according to the proceduredescribed in step 5 of Example 40 from6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine(step 6).

[1884]¹H-NMR (CDCl₃) δ 7.70 (1H, s), 7.55 (2H, d, J=7.9 Hz), 7.50 (2H,d, J=7.9 Hz), 7.13 (1H, s), 3.95 (2H, t, J=7.0 Hz), 3.16 (2H, t, J=7.0Hz), 2.97 (3H, s), 2.71 (2H, q, J=7.6 Hz), 1.21 (3H, t, J=7.6 Hz).

[1885] Step 8.N-{1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide

[1886] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 fromN-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide(step 7).

[1887]¹H-NMR (CDCl₃) δ 7.47 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz),7.16 (1H, s), 6.78 (1H, s), 3.63 (2H, t, J=6.9 Hz), 2.98-3.05 (5H, m),2.77 (2H, q, J=7.4 Hz), 1.35 (3H, t, J=7.4 Hz).

[1888] Step 9.N-{1-[4-(2-Aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide

[1889] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 fromN-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide(step 8).

[1890]¹H-NMR (CDCl₃) δ 8.03 (1H, s), 7.43 (2H, d, J=8.4 Hz), 7.26 (2H,d, J=8.4 Hz), 7.17 (1H, s), 3.33 (2H, br.s), 3.08 (2H, t, J=7.0 Hz),2.96 (3H, s), 2.88 (2H, t, J=7.0 Hz), 2.77 (2H, q, J=7.6 Hz), 1.35 (3H,t, J=7.6 Hz).

[1891] Step 10.6-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-[(methylsulfonyl)amino]-1H-benzimidazole

[1892] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 fromN-{1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide(step 9).

[1893] mp 101-123° C.; MS (ESI) m/z 590 (M+H)⁺; ¹H-NMR (CDCl₃) δ 8.04(1H, s), 7.73 (2H, d, J=8.2 Hz), 7.42 (2H, d, J=8.2 Hz), 7.25-7.33 (4H,m), 7.16 (1H, s), 6.68 (1H, br.s), 3.58 (2H, t, J=7.2 Hz), 2.93-2.98(5H, m), 2.77 (2H, q, J=7.5 Hz), 2.45 (3H, s), 1.35 (3H, t, J=7.5 Hz);IR (KBr) ν_(max) 1654, 1517, 1467, 1336, 1151, 1089, 972 cm⁻¹.

Example 1116-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

[1894] Step 1.2-Chloro-4-[4-(2-hydroxyethyl)anilino]-5-nitrobenzonitrile

[1895] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2,4-dichloro-5-nitrobenzonitrile(Grivsky, E. M.; Hitchings, G. H. Ind. Chim. Belge., 1974, 39. 490.) and4-aminophenylethyl alcohol.

[1896]¹H-NMR (CDCl₃) δ 9.81 (1H, br.s), 8.56 (1H, s), 7.39 (2H, d, J=8.3Hz), 7.23 (2H, d, J=8.3 Hz), 7.15 (1H, s), 3.93 (2H, t, J=6.2 Hz), 2.94(2H, t, J=6.2 Hz), 1.62 (1H, br.s).

[1897] Step 2.5-amino-2-chloro-4-[4-(2-hydroxyethyl)anilino]benzonitrile

[1898] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-chloro-4-[4-(2-hydroxyethyl)anilino]-5-nitrobenzonitrile (step 1).

[1899]¹H-NMR (CDCl₃) δ 7.23 (4H, d, J=8.3 Hz), 6.99-7.33 (2H, m), 3.88(2H, t, J=6.1 Hz), 3.56 (1H, br.s), 2.87 (2H, t, J=6.1 Hz).

[1900] Step 3.2-[4-(6-Chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[1901] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from5-amino-2-chloro-4-[4-(2-hydroxyethyl)anilino]benzonitrile (step 2) andpropionyl chloride.

[1902] TLC Rf=0.5 (hexane/ethyl acetate=1:2).

[1903] Step 4.6-Chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile

[1904] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(6-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate (step 3).

[1905]¹H-NMR (CDCl₃) δ 8.04 (1H, s), 7.52 (2H, d, J=8.4 Hz), 7.29 (2H,d, J=8.4 Hz), 7.19 (1H, s), 4.02 (2H, t, J=6.5 Hz), 3.03 (2H, t, J=6.5Hz), 2.80 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).

[1906] Step 5.6-Chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide

[1907] To a mixture of6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile(step 4, 2.4 g, 7.4 mmol), DMSO (0.7 mL, 8.8 mmol) and methanol (100 mL)was added 30% aqueous hydrogen peroxide (1.3 mL, 11 mmol) and 0.2 Maqueous NaOH (0.7 mL, 0.14 mmol). The mixture was stirred at 50° C. for2 h. The solvent was removed and the resulting precipitates werecollected by filtration. The precipitates were washed with water anddried under reduced pressure to give 1.9 g (76%) of the title compoundas pale pink solids: ¹H-NMR (DMSO-d₆) δ 7.69 (1H, br.s), 7.61 (1H, s),7.33-7.40 (4H, m), 6.95 (1H, s), 4.64 (1H, br.s), 3.59 (2H, t, J=6.4Hz), 2.74 (2H, t, J=6.4 Hz), 2.62 (2H, q, J=7.4 Hz), 1.11 (3H, t, J=7.4Hz).

[1908] Step 6.6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide

[1909] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (step 5).

[1910]¹H-NMR (DMSO-d₆) δ 7.71 (1H, br.s), 7.62 (1H, s), 7.36-7.47 (5H,m), 6.95 (1H, s), 3.85 (2H, t, J=7.1 Hz), 3.06 (2H, t, J=7.1 Hz), 2.63(2H, q, J=7.6 Hz), 1.11 (3H, t, J=7.6 Hz).

[1911] Step 7.1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide

[1912] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide(step 6).

[1913]¹H-NMR (DMSO-d₆) δ 7.80 (1H, br.s), 7.71 (1H, s), 7.46-7.57 (5H,m), 7.04 (1H, s), 3.65 (2H, t, J=6.9 Hz), 2.98 (2H, t, J=6.9 Hz), 2.72(2H, q, J=7.5 Hz), 1.21 (3H, t, J=7.5 Hz).

[1914] Step 8.1-[4-(2-Aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide

[1915] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide(step 7).

[1916]¹H-NMR (CDCl₃) δ 7.80 (1H, s), 7.71 (1H, s), 7.39-7.50 (5H, m),7.08 (1H, s), 2.49-2.89 (6H, m), 1.21 (3H, t, J=7.4 Hz).

[1917] Step 9.6-Chloro-2-ethyl-1-(4-{2-[({[(4-methyltphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

[1918] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide(step 8).

[1919] mp 152-163° C.; MS (ESI) m/z 540 (M +H)⁺; ¹H-NMR (DMSO-d₆) δ 7.81(1H, br.s), 7.72-7.75 (3H, m), 7.51 (1H, br.s), 7.33-7.44 (6H, m), 7.06(1H, s), 3.26 (2H, br.s), 2.68-2.80 (4H, m), 2.34 (3H, s), 1.23 (3H, t,J=7.5 Hz); IR (KBr) ν_(max) 3395, 1664, 1519, 1396, 1161, 1089, 991cm⁻¹.

Example 1126-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxlicacid

[1920] A mixture of6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide(Example 111, 140 mg, 0.26 mmol) and KOH (63 mg, 0.8 mmol) in methanol(10 mL) was stirred at 100° C. for 1 day. The mixture was poured intowater, acidified with 2N hydrochloric acid, and extracted with ethylacetate (50 mL). The organic layer was washed with brine (30 mL), dried(Na₂SO₄), and concentrated. The residue was purified by flash columnchromatography on silica gel eluting with dichloromethane/mathanol(10:1) to afford 36 mg (25%) of the title compound as white solids: mp145-150° C.; MS (ESI) m/z 541 (M+H)⁺; ¹H-NMR (DMSO-d₆) δ 8.10 (1H, s),7.76 (2H, d, J=7.9 Hz), 7.36-7.47 (6H, m), 7.10 (1H, s), 3.28 (2H, m),2.69-2.81 (4H, m), 2.34 (3H, s), 1.24 (3H, t, J=7.5 Hz); IR (KBr) v.,:3450, 1701, 1517, 1340, 1163, 1091, 900 cm⁻¹.

Example 113N-[6-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzomidazol-5-yl]acetamide

[1921] Step 1.N-{6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}acetamide

[1922] To a solution of6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine(step 6 of Example 110, 100 mg, 0.3 mmol) in pyridine (7 mL) was addeddropwise acetyl chloride (0.03 mL, 0.33 mmol) under nitrogen atmosphereat 0° C., and the reaction mixture was stirred at room temperature for1.5 h. The mixture was poured into water (20 mL) and extracted withethyl acetate (50 mL). The organic layer was washed with 2N aqueous NaOH(30 mL), brine (30 mL), then dried (Na₂SO₄). After removal of solvent,the crude product was purified by flash column chromatography on silicagel eluting with hexane/ethyl acetate (1:3) to afford 110 mg (98%) ofthe title compound as white solids: ¹H-NMR (CDCl₃) δ: 8.66 (1H, s), 7.56(1H, br.s), 7.45 (2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz), 7.12 (1H,s), 3.82 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 2.77 (2H, q, J=7.6Hz), 2.26 (3H, s), 1.34 (3H, t, J=7.6 Hz).

[1923] Step 2.N-{1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}acetamide

[1924] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 fromN-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}acetamide(step 1).

[1925]¹H-NMR (DMSO-d₆) δ 8.66 (1H, s), 7.55 (1H, br.s), 7.45 (2H, d,J=8.1 Hz), 7.30 (2H, d, J=8.1 Hz), 7.11 (1H, s), 3.62 (2H, t, J=7.1 Hz),3.02 (2H, t, J=7.1 Hz), 2.76 (2H, q, J=7.6 Hz), 2.26 (3H, s), 1.34 (3H,t, J=7.6 Hz).

[1926] Step 3.N-{1-[4-(2-Aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}acetamide

[1927] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 fromN-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}acetamide(step 2).

[1928]¹H-NMR (CDCl₃) δ 8.66 (1H, s), 7.55 (1H, br.s), 7.42 (2H, d, J=6.6Hz), 7.27-7.29 (2H, m), 7.12 (1H, s), 3.08 (2H, t, J=6.9 Hz), 2.88 (2H,t, J=6.9 Hz), 2.75 (2H, q, J=7.4 Hz), 2.26 (3H, s), 1.34 (3H, t, J=7.4Hz).

[1929] Step 4.N-[6-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazol-5-yl]acetamide

[1930] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 fromN-{1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}acetamide(step 3).

[1931] mp 125-133° C.; MS (ESI) m/z 554 (M+H)⁺; ¹H-NMR (CDCl₃) δ 8.64(1H, s), 7.74 (2H, d, J=8.4 Hz), 7.55 (1H, br.s), 7.25-7.39 (1H, s),7.08 (1H, s), 3.53-3.61 (2H, m), 2.94 (2H, t, J=7.1 Hz), 2.75 (2H, q,J=7.4 Hz), 2.41 (3H, s), 2.27 (3H, s), 1.32 (3H, t, J=7.4 Hz); IR (KBr)ν_(max) 3390, 1676, 1517, 1240, 1161, 1089, 1018, 972 cm⁻¹.

Example 1146-Ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole

[1932] Step 1. 2-{4-[(6-Nitro-1,3-benzodioxol-5-yl)amino]phenyl}ethanol

[1933] The title compound was prepared according to the proceduredescribed in step 1 of Example 45 from 5-amino-6-nitro-1,3-benzodioxoland 4-bromophenylethyl alcohol.

[1934]¹H-NMR (CDCl₃) δ:10.07 (1H, br.s), 7.62 (1H, s), 7.29 (2H, d,J=8.5 Hz), 7.20 (2H, d, J=8.5 Hz), 6.58 (1H, s), 5.98 (2H, s), 3.90 (2H,t, J=6.6 Hz), 2.90 (2H, t, J=6.6 Hz).

[1935] Step 2. 2-{4-[(6-Amino-1,3-benzodioxol-5-yl)amino]phenyl}ethanol

[1936] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{4-[(6-nitro-1,3-benzodioxol-5-yl)amino]phenyl}ethanol (step 1).

[1937]¹H-NMR (CDCl₃) δ 7.26 (1H, s), 7.04 (2H, d, J=8.2 Hz), 6.60 (2H,d, J=8.2 Hz), 6.39 (1H, s), 5.87 (2H, s), 4.96 (1H, br.s), 3.80 (2H, t,J=6.4 Hz), 3.64 (2H, br.s), 2.76 (2H, t, J=6.4 Hz).

[1938] Step 3.2-[4-(6-Ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazol-5-yl)phenyl]ethylproiionate

[1939] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(6-amino-1,3-benzodioxol-5-yl)amino]phenyl}ethanol (step 2) andpropionyl alcohol.

[1940] TLC Rf=0.5 (hexane/ehtyl acetate=1:2).

[1941] Step 4.2-[4-(6-Ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazol-5-yl)phenyl]ethanol

[1942] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[(6-amino-1,3-benzodioxol-5-yl)amino]phenyl}ethyl propionate (step3).

[1943]¹H-NMR (CDCl₃) δ 7.43 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz),7.19 (1H, s), 6.53 (1H, s), 5.94 (2H, s), 3.98 (2H, t, J=6.4 Hz), 2.99(2H, t, J=6.4 Hz), 2.73 (2H, q, J=7.4 Hz), 1.31 (3H, t, J=7.4 Hz).

[1944] Step 5.5-[4-(2-Chloroethyl)phenyl]-6-ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazole

[1945] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(6-ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazol-5-yl)phenyl]ethanol(step 4).

[1946]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.1 Hz), 7.28 (2H, d, J=8.1 Hz),7.19 (1H, s), 6.54 (1H, s), 5.94 (2H, s), 3.81 (2H, t, J=7.1 Hz), 3,19(2H, t, J=7.1 Hz), 2.72 (2H, q, J=7.6 Hz), 1.31 (3H, t, J=7.6 Hz).

[1947] Step 6.2-[4-(6-Ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazol-5-yl)phenyl]ethyl azide

[1948] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from5-[4-(2-chloroethyl)phenyl]-6-ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazole(step 5).

[1949]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz),7.19 (1H, s), 6.53 (1H, s), 5.93 (2H, s), 3.60 (2H, t, J=7.1 Hz), 3.00(2H, t, J=7.1 Hz), 2.73 (2H, q, J=7.6 Hz), 1.31 (3H, t, J=7.6 Hz).

[1950] Step 7.2-[4-(6-Ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazol-5-yl)phenyl]ethylamine

[1951] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(6-ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazol-5-yl)phenyl]ethyl azide(step 6).

[1952]¹H-NMR (CDCl₃) δ 7.40 (2H, d, J=8.2 Hz), 7.22-7.28 (2H, m), 7.19(1H, s), 6.54 (1H, s), 5.93 (2H, s), 3.05 (2H, t, J=6.8 Hz), 2.86 (2H,t, J=6.8 Hz), 2.73 (2H, q, J=7.6 Hz), 1.31 (3H, t, J=7.6 Hz).

[1953] Step 8.6-Ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole

[1954] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(6-ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazol-5-yl)phenyl]ethylamine(step 7).

[1955] MS (ESI) m/z 507 (M+H)⁺; ¹H-NMR (DMSO-d₆) δ 7.75 (2H, d, J=8.1Hz), 7.35-7.37 (6H, m), 7.16 (1H, s), 6.55 (1H, s), 5.97 (2H, s), 2.76(2H, t, J=6.9 Hz), 2.65 (2H, q, J=7.6 Hz), 2.50 (2H, br.s), 2.34 (3H,s), 1.18 (3H, t, J=7.6 Hz).

Example 1156-Ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole,sodium salt

[1956] The title compound was prepared according to the proceduredescribed in Example 2 from6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole(Example 114).

[1957] mp 140-155° C.; IR (KBr) ν_(max) 3384, 2873, 1600, 1519, 1460,1155, 1128, 1085, 1037, 945, 813 cm⁻¹.

Example 1162-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazole

[1958] Step 1. 7-Nitro-2,3-dihydro-1,4-benzodioxin-6-amine

[1959] To a mixture of 6,7-dinitro-2,3-dihydrobenzo[1,4]dioxin (Takakis,I. M.; Hadjimihalakis, P. M. J. Heterocyclic. Chem., 1991, 28, 625., 13g, 57.8 mmol) and acetic acid (150 mL) was added iron powder (9.6 g,172.5 mmol) at room temperature, then the mixture was refluxed for 30min. After cooling, the mixture was filtered through a pad of Celite andthe filtrate was concentrated. The residue was purified by flash columnchromatography on silica gel eluting with hexane/ethyl acetate (gradientelution from 1:1 to 1:2) to afford 3.22 g (28%) of the title compound asorange solid: ¹H-NMR (CDCl₃) δ 7.67 (1H, s), 6.23 (1H, s), 5,85 (2H,br.s), 4.19-4.33 (4H, m).

[1960] Step 2.2-{4-[(7-Nitro-2,3-dihydro-1,4-benzodioxin-6-yl)amino]phenyl}ethanol

[1961] The title compound was prepared according to the proceduredescribed in step 1 of Example 45 from7-nitro-2,3-dihydro-1,4-benzodioxin-6-amine (step 1) and4-bromophenylethyl alcohol.

[1962]¹H-NMR (CDCl₃) δ 7.77 (1H, s), 7.26 (2H, d, J=8.4 Hz), 7.19 (2H,d, J=8.4 Hz), 6.64 (1H, s), 4.20-4.31 (4H, m), 3.89 (2H, t, J=6.4 Hz),2.88 (2H, t, J=6.4 Hz).

[1963] Step 3.2-{4-[(7-Amino-2,3-dihydro-1,4-benzodioxin-6-yl)amino]phenyl}ethanol

[1964] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{4-[(7-nitro-2,3-dihydro-1,4-benzodioxin-6-yl)amino]phenyl}ethanol(step 2).

[1965]¹H-NMR (CDCl₃) δ 7.02-7.05 (2H, m), 6.62-6.65 (3H, m), 6.33 (1H,s), 5.00 (1H, br.s), 4.15-4.24 (4H, m), 3.79 (2H, t, J=6.6 Hz), 3.53(2H, br.s), 2.76 (2H, t, J=6.6 Hz).

[1966] Step 4.2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazol-1-yl)phenyl]ethylpropionate

[1967] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)amino]phenyl ethanol(step 3) and propionyl chloride.

[1968] TLC Rf=0.5 (hexane:ethyl acetate=1:2).

[1969] Step 5.2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazol-1-yl)phenyl]ethanol

[1970] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)amino]phenyl}ethylpropionate (step 4).

[1971]¹H-NMR (CDCl₃) δ 7.42 (2H, d, J=8.1 Hz), 7.25-7.28 (3H, m), 6.58(1H, s), 4.21-4.27 (4H, m), 3.97 (2H, t, J=6.6 Hz), 2.98 (2H, t, J=6.6Hz), 2.74 (2H, q, J=7.3 Hz), 1.31 (3H, t, J=7.3 Hz).

[1972] Step 6.1-[4-(2-Chloroethyl)phenyl]-2-ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazole

[1973] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazol-1-yl)phenyl]ethanol(step 5).

[1974]¹H-NMR (CDCl₃) δ 7.40 (2H, d, J=8.1 Hz), 7.26-7.39 (3H, m), 6.58(1H, s), 4.25 (4H, s), 3.80 (2H, t, J=7.3 Hz), 3.20 (2H, t, J=7.3 Hz),2.74 (2H, q, J=7.6 Hz), 1.31 (3H, t, J=7.6 Hz).

[1975] Step 7.2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazol-1-yl)phenyl]ethylazide

[1976] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazole(step 6).

[1977]¹H-NMR (CDCl₃) δ 7.40 (2H, d, J=8.3 Hz), 7.24-7.29 (3H, m), 6.57(1H, s), 4.21-4.26 (4H, m), 3.59 (2H, t, J=7.0 Hz), 2.99 (2H, t, J=7.0Hz), 2.73 (2H, q, J=7.5 Hz), 1.30 (3H, t, J=7.5 Hz).

[1978] Step 8.2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazol-1-yl)phenyl]ethylamine

[1979] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(2-ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazol-1-yl)phenyl]ethylazide (step 6).

[1980]¹H-NMR (CDCl₃) δ 77.40 (2H, d, J=8.3 Hz), 7.24-7.27 (3H, m), 6.62(1H, s), 4.21 (4H, s), 3.24-3.26 (2H, m), 3.11 (2H, t, J=6.9 Hz), 2.72(2H, q, J=7.4 Hz), 1.30 (3H, t, J=7.4 Hz).

[1981] Step 9.2-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazole

[1982] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazol-1-yl)phenyl]ethylamine(step 8).

[1983] MS (ESI) m/z 521 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.76 (2H, d, J=8.4 Hz),7.18-7.31 (7H, m), 6.64 (1H, br.s), 6.56 (1H, br.s), 4.24 (4H, s), 3.56(2H, t, J=6.9 Hz), 2.90 (2H, t, J=6.9 Hz), 2.70 (2H, q, J=7.6 Hz), 2.41(3H, s), 1.27 (3H, t, J=7.6 Hz).

Example 1172-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazole,sodium salt

[1984] The title compound was prepared according to the proceduredescribed in Example 2 from2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazole(Example 116).

[1985] mp 162-173° C.; ¹H-NMR (DMSO-d₆) δ 7.83 (2H, d, J=8.0 Hz), 7.58(2H, d, J=8.6 Hz), 7.54 (2H, d, J=8.0 Hz), 7.35 (2H, d, J=8.6 Hz), 7.29(1H, s), 6.68 (1H, s), 4.42 (4H, s), 3.38 (2H, br.s), 2.94 (2H, t, J=6.9Hz), 2.86 (2H, q, J=7.6 Hz), 2.49 (3H, s), 1.39 (3H, t, J=7.6 Hz); IR(KBr) ν_(max) 3360, 2875, 1596, 1516, 1468, 1335, 1167, 1130, 1064, 920cm⁻¹.

Example 118-Example 161

[1986] The compounds disclosed hereinafter were prepared according tothe following procedure: To a solution of requisite commerciallyavailable sulfonamide (0.05 mmol) in DMF (1 mL) was added a suspensionof NaH (0.1 mmol) in DMF (0.5 mL) and the mixture was shaken for 5 min.To this mixture was added a solution of phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 18, 7 mg, 0.05 mmol) in DMF (0.5 mL), and the mixturewas shaken at room temperature for 30 min. After removal of DMF bynitrogen blow, the residue was dissolved in water (3 mL) and loaded ontoa 0.5 g/3 mL BondElute SCX. The solid phase was washed with MeOH (5 mL),and then eluted with 10% HCl/MeOH (3 mL). The eluate was concentratedunder reduced pressure to give the title compound.

Example 1183-(4-{2-[({[(3,4-Diclorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1987] MS (ESI) m/z 546.6 (M+H)⁺.

Example 1192-Ethyl-3-{4-[2-({[({3-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1988] MS (ESI) m/z 523.3 (M+H)⁺.

Example 1203-(4-{2-[({[(4-Chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1989] MS (ESI) m/z 512.5 (M+H)⁺.

Example 1212-Ethyl-3-{4-[2-({[({4-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1990] MS (ESI) m/z 523.3 (M+H)⁺.

Example 122N-[4-({[({2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phentyl]ethyl}amino)carbonyl]amino}sulfonyl)phenyl]-2,2-dimethylpropanamide,hydrochloride

[1991] MS (ESI) m/z 577.5 (M+H)⁺.

Example 1233-(4-{2-[({[(2-Chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1992] MS (ESI) m/z 512.4 (M+H)⁺.

Example 1243-(4-{2-[({[(3-Chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1993] MS (ESI) m/z 512.5 (M+H)⁺.

Example 1253-(4-{2-[({[(5-Chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1994] MS (ESI) m/z 518.6 (M+H)⁺.

Example 1263-(4-{2-[({[(5-Bromo-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1995] MS (ESI) m/z 564.2 (M+H)⁺.

Example 1272-Ethyl-3-{4-[2-({[({2-methyl-5-nitro-phenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1996] MS (ESI) m/z 537.3 (M+H)⁺.

Example 1283-(4-{2-[({[(3,4-Dimethoxyphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1997] MS (ESI) m/z 538.4 (M+H)⁺.

Example 1293-(4-{2-[({[(4-Butylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1998] MS (ESI) m/z 534.5 (M+H)⁺.

Example 1302-Ethyl-3-(4-{2-[({[(4-methoxyphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[1999] MS (ESI) m/z 508.4 (M+H)⁺.

Example 1312-Ethyl-5,7-dimethyl-3-[4-(2-{[({[5-(phenylsulfanyl)-2-thienyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine,hydrochloride

[2000] MS (ESI) m/z 592.4 (M+H)⁺.

Example 1323-(4-{2-[({[(3,5-Dichlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}pheyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2001] MS (ESI) m/z 546.6 (M+H)⁺.

Example 1333-(4-{2-[({[(2-Bromophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2002] MS (ES) m/z 558.0 (M+H)⁺.

Example 1343-(4-{2-[({[(4,5-Dichloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2003] MS (ESI) adz 552.6 (M+H)⁺.

Example 1353-[4-(2-{[{[2-(2,4-Dichlorophenoxy)phenyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2004] MS (ESI) m/z 638.8 (M+H)⁺.

Example 1363-(4-{2-[({[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2005] MS (ESI) m/z 530.3 (M+H)⁺.

Example 1373-(4-{2-[({[(2,4-Dimethyl-1,3-thiazol-5-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2006] MS (ESI) m/z 523.2 (M+H)⁺.

Example 1383-(4-{2-[({[(4-Cyanophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2007] MS (ESI) m/z 503.2 (M+H)⁺.

Example 1393-(4-{2-[({[(3,4-Difluorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2008] MS (ESI) mz 514.3 (M+H)⁺.

Example 1403-(4-{2-[({[(2,5-Dichloro-3-thienyl)sulfonyl]amino}carbonyl)aminoethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2009] MS (ESI) m/z 552.3 (M+H)⁺.

Example 141N-[5-({[({2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)-1,3,4-thiadiazol-2-yl]acetamide,hydrochloride

[2010] MS (ESI) m/z 543.0 (M+H)⁺.

Example 1423-{4-[2-({[({4-Chloro-3-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2011] MS (ESI) m/z 557.2 (M+H)⁺.

Example 1433-(4-{2-[({[(4-Butoxyphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2012] MS (ESI) m/z 550.4 (M+H)⁺.

Example 1443-[4-(2-{[({[2,6-Dichloro-4-(trifluoromethyl)phenyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2013] MS (ESI) mz 614.4 (M+H)⁺.

Example 1453-[4-(2-{[({[4-(1-Adamantyl)phenyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2014] MS (ESI) m/z 612.4 (M+H)⁺.

Example 1463-(4-{2-[({[(4,5-Dibromo-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2015] MS (ESI) m/z 642.0 (M+H)⁺.

Example 1472-Ethyl-5,7-dimethyl-3-[4-(2-{[({[5-(2-thienylsulfanyl)-2-thienyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine,hydrochloride

[2016] MS (ESI) m/z 598.2 (M+H)⁺.

Example 1483-(4-{2-[({[(4-tert-Butylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2017] MS (ESI) m/z 534.4 (M+H)⁺.

Example 1493-(4-{2-[({[(4-Amino-3-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ehyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2018] MS (ESI) m/z 527.3 (M+H)⁺.

Example 1502-Ethyl-5,7-dimethyl-3-(4-{2-[({[(2,4,5-trichlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,hydrochloride

[2019] MS (ESI) m/z 580.4 (M+H)⁺.

Example 1513-(4-{2-[({[(2,5-Dimethoxyphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2020] MS (ESI) m/z 538.3 (M+H)⁺.

Example 1523-(4-{2-[({[(6-Ethoxy-1,3-benzothiazol-2-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2021] MS (ESI) m/z 579.1 (M+H)⁺.

Example 1533-(4-{2-[({[(2-Amino-4-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2022] MS (ESI) m/z 527.2 (M+H)⁺.

Example 1542-Ethyl-5,7-dimethyl-3-[4-(2-{[({[5-(2-thienylsulfonyl)-2-thienyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine,hydrochloride

[2023] MS (ESI) m/z 630.2 (M+H)⁺.

Example 1553-[4-(2-{[({[2-Chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2024] MS (ESI) mz 580.2 (M+H)⁺.

Example 1563-{4-[2-({[(2,3-Dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2025] MS (ESI) m/z 536.2 (M+H)⁺.

Example 1572-Ethyl-5,7-dimethyl-3-[4-(2-{[({[2-(phenylsulfanyl)phenyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine,hydrochloride

[2026] MS (ESI) m/z 586.3 (M+H)⁺.

Example 1583-(4-{2-[({[(4-Chloro-2,5-dimethylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2027] MS (ESI) m/z 540.3 (M+H)⁺.

Example 1593-(4-{2-[({[(3-Bromo-5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,hydrochloride

[2028] MS (ESI) m/z 598.1 (M+H)⁺.

Example 1602-Ethyl-5,7-dimethyl-3-(4-{2-[({[(4-vinylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,hydrochloride

[2029] MS (ESI) m/z 504.4 (M+H)⁺.

Example 161 Methyl2,4-dichloro-5-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)benzoate,hydrochloride

[2030] MS (ESI) m/z 604.5 (M+H)⁺.

Example 162-Example 194

[2031] The compounds disclosed hereinafter were prepared according tothe following procedure: To a mixture of requisite commerciallyavailable carbonic acid and dichloromethane was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (WSC) (0.05mmol, 0.5 mL), then to the reaction mixture was added a solution of3-amino-4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}anilino)pyridine*(0.038 mmol) in dichloromethane (0.5 mL) at room temperature. Thereaction mixture was stirred for 3 days at room temperature, thenstirred for an additional 1 day at 40° C. After removal of the solvent,the residue was dissolved in MeOH (1 mL) and the solution was filteredthrough a membrane filter. The filtrate was purified by preparativeLC/MS (Shiseido capcell pack UG80 C18 (4.6×50 mm) eluting with MeOH/0.1%HCOOH (v/v, 20/80 to 90/10)) to give the title compound.

[2032]3-amino-4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}anilino)pyridinewas prepared as follows;

[2033] Step 1,3-{4-[(4,6-Dimethyl-3-nitro-2-pvridinyl)aminolphenyl]propanoic Acid

[2034] To a solution of 2-chloro-4,6-dimethyl-3-nitropyridine (17.9 g,96 mmol) and methyl 3-(4-aminophenyl)propanoate (19 g, 96 nmol) in DMSO(100 mL) was added N,N-diisopropylethylamine (26 g, 200 mmol), and thereaction mixture was heated at 140° C. overnight. The reaction mixturewas partitioned between water (400 mL) and ethyl acetate/toluene (v/v,2:1, 300 mL). The organic phase was separated and the aqueous phase wasextracted with ethyl acetate/toluene (v/v, 2:1, 200 mL). The combinedorganic extracts were washed with brine (200 mL), dried (Na₂SO₄), andconcentrated. To a solution of residual oil in methanol (100 mL) wasadded 2 N aqueous NaOH (150 mL, 300 mmol) and the resulting mixture wasstirred at room temperature for 2 h. The volatile component was removedunder reduced pressure and the residue was washed with ethyl acetate(200 mL). The aqueous phase was acidified with 2N hydrochloric acid (200mL, 400 mmol) and extracted with ethyl acetate (3×200 mL). The extractswere washed with brine (200 ML), dried (Na₂SO₄), and concentrated togive 23.2 g (77%) of the title compound as pale brown solids.

[2035]¹H-NMR (CDCl₃) δ: 9.57 (1H, s), 7.56 (2H, d, J=8.4 Hz), 7.19 (2H,d, J=8.4 Hz), 6.52 (1H, s), 2.95 (2H, t, J=7.5 Hz), 2.66 (2H, t, J=7.5Hz), 2.55 (3H, s), 2.43 (3H, s).

[2036] Step 2, Phenyl2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethylcarbamate

[2037] To a stirred solution of3-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}propanoic acid(step 1, 10 g, 31.7 mmol) in dioxane (200 mL) was addeddiphenylphosphoryl azide (DPPA) (7.54 ml, 35 mmol) and triethylamine(4.87 mL, 35 mmol). The reaction mixture was heated at 120° C. for 2 h.To the reaction mixture was added phenol (6.6 g, 70 mmol) and thereaction mixture was refluxed. After 3 h, to the reaction mixture wasadded an additional amount of phenol (3.3 g, 35 mmol). The resultingmixture was heated under reflux temperature overnight. The volatilecomponent was removed and the residue was partitioned between aqueous10% aqueous citric acid (200 mL) and ethyl acetate (300 mL). The organicphase was separated and the aqueous phase was extracted with ethylacetate (300 mL). The combined organic extracts were washed with water(300 mL) and brine (300 mL), then dried (Na₂SO₄), and concentrated. Thecrude product was purified by flash column chromatography on silica geleluting with hexane/EtOAc (2:1) to afford 10.3 g (77%) of the titlecompound as orange solids.

[2038]¹H-NMR (CDCl₃) δ: 9.60 (1H, s), 7.61 (2H, d, J=8.6 Hz), 7.38-7.32(2H, m), 7.24-7.16 (3H, m), 7.14-7.09 (2H, m), 6.54 (1H, s), 5.06 (1H,br.s), 3.58-3.50 (2H, m), 2.89 (2H, t, J=6.9 Hz), 2.56 (3H, s), 2.44(3H, s).

[2039] Step 3,4,6-Dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}anilino)-3-nitropyridine

[2040] To a stirred solution of phenyl2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethylcarbamate(step 2, 10.0 g, 24.6 mmol) and p-toluenesulfonamide (6.3 g, 36.8 rnmol)in DMF (100 mL) was added sodium hydride (2.0 g, 50 mmol). The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas poured into water (300 mL) and extracted with ethyl acetate/toluene(v/v, 2:1, 2×300 mL). The organic extracts were washed with water (100mL) and brine (200 mL), then dried (Na₂SO₄). Removal of the solvent gavecrude product. Recrystallization from ethyl acetate gave 9.6 g (81%) ofthe title compound as brown solids. The mother liquor was concentratedand the residue was purified by flash column chromatography on silicagel eluting with hexane/ethyl acetate (1:1) to afford 1.9 g (16%) of thetitle compound as brown solids.

[2041]¹H-NMR (CDCl₃) δ: 9.75 (1H, s), 7.62 (2H, d, J=8.4 Hz), 7.59 (2H,d, J=8.4 Hz), 7.26 (2H, d, J=8.4 Hz), 7.15 (2H, d, J=8.4 Hz), 6.62-6.50(2H, m), 3.55-3.42 (2H, m), 2.80 (2H, t, J=6.9 Hz), 2.56 (3H, s), 2.43(3H, s), 2.39 (3H, s).

[2042] Step 4,3-Amino-4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}anilino)pyridine

[2043] To a solution of4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}anilino)-3-nitropyridine(step 3, 11.4 g, 23.6 mmol) in methanol (250 mL) was added 10% Pd—C (2.0g). The resulting mixture was stirred under the medium pressure ofhydrogen (4.0 kgf/cm²) for 4 h. The catalyst was removed by filtration,and the filtrate was concentrated. The residue was recrystallized fromethyl acetate to afford 9.0 g (85%) of the title compound as off whitesolids.

[2044]¹H-NMR (CDCl₃) δ: 7.69 (2H, d, J=8.0 Hz), 7.26 (2H, d, J=8.0 Hz),7.00-6.95 (4H, m), 6.61 (1H, s), 6.24 (1H, br.s), 3.44-3.38 (2H, m),2.70 (2H, t, J=6.7 Hz), 2.39 (3H, s), 2.33 (3H, s), 2.19 (3H, s).

Example 1625,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[3-oxo-3-(2-thienyl)propyl]-3H-imidazo[4,5-b]pyridine,formate

[2045] MS (ESI) m/z 602.48 (M+H)⁺.

Example 1635,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(phenoxymethyl)-3H-imidazo[4,5-b]pyridine,formate

[2046] MS (ESI) m/z 570.5 (M+H)⁺.

Example 1645,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(3-pyridinyl)ethyl]-3H-imidazo[4,5-b]pyridine,formate

[2047] MS (ESI) m/z 569.49 (M+H)⁺.

Example 1655,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(3-oxo-3-phenylpropyl)-3H-imidazo[4,5-b]pyridine,formate

[2048] MS (ESI) m/z 596.28 (M+H)⁺.

Example 1665,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(3-phenylpropyl)-3H-imidazo[4,5-b]pyridine,formate

[2049] MS (ESI) m/z 582.52 (M+H)⁺.

Example 1672-(Ethoxymethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,formate

[2050] MS (ESI) m/z 522.46 (M+H)⁺.

Example 1685,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[(phenylsulfanyl)methyl]-3H-imidazo[4,5-b]pyridine,formate

[2051] MS (ESD m/z 586.49 (M+H)⁺.

Example 1695,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-pentyl-3H-imidazo[4,5-b]pyridine,formate

[2052] MS (ESI) m/z 534.51 (M+H)⁺.

Example 1705,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(2-phenylethyl)-3H-imidazo[4,5-b]pyridine,formate

[2053] MS (ESI) m/z 568.51 (M+H)⁺.

Example 1712-(3-Butynyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,formate

[2054] MS (ESI) m/z 516.45 (M+H)⁺.

Example 1725,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(3-thienylmethyl)-3H-imidazo[4,5-b]pyridine,formate

[2055] MS (ESI) m/z 560.44 (M+H)⁺.

Example 1735,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(4-pentynyl)-3H-imidazo[4,5-b]pyridine,formate

[2056] MS (ESI) f/z 530.46 (M+H)⁺.

Example 1745,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(2-thienylmethyl)-3H-imidazo[4,5-b]pyridine,formate

[2057] MS (ESI) m/z 560.44 (M+H)⁺.

Example 1755,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(3-pyridinylmethyl)-3H-imidazo[4,5-b]pyridine,formate

[2058] MS (ESI) m/z 555.48 (M+H)⁺.

Example 1765,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[(2E)-2-pentenyl]-3H-imidazo[4,5-b]pyridine,formate

[2059] MS (ESI) m/z 532.48 (M+H)⁺.

Example 1772-Benzyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,formate

[2060] MS (ESI) m/z 554.48 (M+H)⁺.

Example 1782-(Cyanomethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,formate

[2061] MS (ESI) m/z 503.41 (M+H)⁺.

Example 1792-(Methoxymethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,formate

[2062] MS (ESI) m/z 508.44 (M+H)⁺.

Example 1802-Heptyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,formate

[2063] MS (ESI) m/z 562.33 (M+H)⁺.

Example 1815,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-octyl-3H-imidazo[4,5-b]pyridine,formate

[2064] MS (ESI) m/z 576.37 (M+H)⁺.

Example 1825,7-Dimethyl-2-(4-methylpentyl)-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,formate

[2065] MS (ESI) m/z 548.53 (M+H)⁺.

Example 1832-[(Benzyloxy)methyl]-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,formate

[2066] MS (ESI) m/z 584.52 (M+H)⁺.

Example 1845,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(2-phenoxyethyl)-3H-imidazo[4,5-b]pyridine,formate

[2067] MS (ESI) m/z 584.33 (M+H)⁺.

Example 1855,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[3-(2-thienyl)propyl]-3H-imidazo[4,5-b]pyridine,formate

[2068] MS (ESI) m/z 588.5 (M+H)⁺.

Example 1865,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(2-naphthylmethyl)-3H-imidazo[4,5-b]pyridine,formate

[2069] MS (ESI) m/z 604.37 (M+H)⁺.

Example 1875,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(4-phenylbutyl)-3H-imidazo[4,5-b]pyridine,formate

[2070] MS (ESI) m/z 596.42 (M+H)⁺.

Example 1885,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(5-phenylpentyl)-3H-imidazo[4,5-b]pyridine,formate

[2071] MS (ESI) m/z 610.45 (M+H)⁺.

Example 1892-(2-Ethoxyethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,formate

[2072] MS (ESI) m/z 536.38 (M+H)⁺.

Example 1902-(2,3-Dihydro-1H-inden-2-ylmethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4.5-b]pyridine,formate

[2073] MS (ESI) m/z 594.45 (M+H)⁺.

Example 1912-(Cyclopropylmethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,formate

[2074] MS (ESI) m/z 518.45 (M+H)⁺.

Example 1925,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(methylsulfanyl)ethyl]-3H-imidazo[4,5-b]pyridine,formate

[2075] MS (ESI) z 538.44 (M+H)⁺.

Example 1932-Hexyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,formate

[2076] MS (ES1) m/z 548.44 (M+H)⁺.

Example 1945,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(4-pentenyl)-3H-imidazo[4,5-b]pyridine,formate

[2077] MS (ESI) m/z 532.42 (M+H)⁺.

Example 1956-Chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[2078] Step 1.6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carbonitrile

[2079] The reaction was carried out according to the procedure describedin step 7 of Example 1 from6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile(Example 111, step 4).

[2080]¹H-NMR (CDCl₃) δ 8.07 (1H, s), 7.50 (2H, d, J=8.4 Hz), 7.30 (2H,d, J=8.4 Hz), 7.19 (1H, s), 3.83 (2H, t, J=7.1 Hz), 3.22 (2H, t, J=7.1Hz), 2.79 (2H, q, J=7.5 Hz), 1.37 (3H, t, J=7.5 Hz).

[2081] Step 2.1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile

[2082] The reaction was carried out according to the procedure describedin step 8 of Example 1 from6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carbonitrile(step 1).

[2083]¹H-NMR (CDCl₃) δ 8.07 (1H, s), 7.49 (2H, d, J=8.4 Hz), 7.29 (2H,d, J=8.4 Hz), 7.18 (1H, s), 3.64 (2H, t, J=7.0 Hz), 3.04 (2H, t, J=7.0Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).

[2084] Step 3.1-[4-(2-Aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile

[2085] The reaction was carried out according to the procedure describedin step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile(step 2).

[2086]¹H-NMR (CDCl₃) δ 8.06 (1H, s), 7.46 (2H, d, J=8.1 Hz), 7.26 (2H,d, J=8.1 Hz), 7.19 (1H, s), 3.09 (2H, t, J=7.1 Hz), 2.89 (2H, t, J=7.1Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).

[2087] Step 4.6-Chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[2088] The reaction was carried out according to the procedure describedin step 10 of Example 1 from1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile(step 3).

[2089] mp 219-224° C.; IR (KBr) ν: 3388, 2229, 1708, 1618, 1514, 1466,1344, 1161, 1089 cm⁻¹.

[2090] MS (ESI) m/z 522 (M+H)⁺, 520 (M−H)⁻; ¹H-NMR (DMSO-d₆) δ 8.38 (1H,s), 7.77 (2H, d, J=8.2 Hz), 7.31-7.49 (6H, m), 7.32 (1H, s), 6.53 (1H,br.s), 3.26-3.28 (2H, m), 2.69-2.81 (4H, m), 2.35 (3H, s), 1.25 (3H, t,J=7.6 Hz).

The Synthetic Procedure of Example 196-Example 197

[2091] The compounds disclosed hereinafter were prepared according tothe following procedure: To a mixture of requisite commerciallyavailable carbonic acid and dichloromethane (DCM) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (WSC) (0.05mmol, 0.5 mL) followed by a solution of3-amino-4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}anilino)pyridine(0.038 mmol) in DCM (0.5 mL) at room temperature. The reaction mixturewas stirred for 3 days at room temperature, then stirred for anadditional day at 40° C. After removal of the solvent, the residue wasdissolved in MeOH (1 mL) and the solution was filtered through amembrane filter. The filtrate was purified by preparative LC/MS(Shiseido capcell pack UG80 C18 (20×50 mm) eluting with MeOH/0.1% HCOOH(v/v, 20/80 to 90/10) to give the title compound.

Example 196N-{[(2-{4-[5,7-Dimethyl-2-(4-methylpentyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,formate

[2092] MS (ESI) ml/z 548.53 (M+H)⁺.

Example 197N-{[(2-{4-[5,7-Dimethyl-2-(3-oxo-3-phenylpropyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}4-methylbenzenesulfonamide,formate

[2093] MS (ESI) m/z 596.28 (M+H)⁺.

The Synthetic Procedure of Example 198-Example 216

[2094] The compounds disclosed hereinafter were prepared according tothe following procedure: The carboxylic acid (0.06 mmol) was dissolvedwith N,N-diisopropylethylamine (DIEA) (0.106 mmol) and dichloromethane(DCM) (0.3 mL). To this mixture was added 1-hydroxybenzotriazole hydrate(HOBT) (0.06 mmol) in N,N-dimethylformamide (DMF) (0.02 mL). To thereaction were added 3-amino-4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}anilino)pyridine(0.044 mmol) in DCM (0.3 mL) and DMF (0.08 mL), thenO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (0.13 mmol) in DMF (0.25 mL). The reaction solution was stirredfor 6 hr at room temperature, then heated at 40° C. over night. Afterremoval of the solvent, the residue was dissolved in MeOH (0.8 mL). Thesolution was loaded onto a Varian BondElute® SCX cartridge (500 mg/3 mL)which was preconditioned with 2 mL of MeOH. The solid-phase matrix waswashed with 5 mL of MeOH and then eluted with 2N ammonia/MeOH (3 mL).After the removal of solvent, the product was used for the next stepreaction.

[2095] The intermediate product of 1^(st) step was dissolved with EtOH(2 mL), then to the reaction solution was added excess 2N aq.NaOH (1mL). The reaction mixture was stirred at 40° C. to 70° C. over night.After the reaction finished, the solvent was removed. To the residue wasadded 2N aq.HCl (1 mL, adjusted with pH 7.0). The aqueous layer wasextracted with DCM (1 mL×3). The organic layer was concentrated toafford the residue. The crude product was purified by preparative LC/MS(Shiseido capcellpack UG 80 C18 (20×50 mm) eluting with MeOH/0.1% HCOOH(v/v, 20/80 to 90/10) to give the title compound as a formate.

Example 198N-{5-[5,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]pentyl}acetamide,formate

[2096] MS (ESI) m/z 591.33 (M+H)⁺.

Example 199N-{[(2-{4-[5,7-Dimethyl-2-(5-oxo-5-phenylpentyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}4-methylbenzenesulfonamide,formate

[2097] MS (ESI) m/z 624.37 (M+H)⁺.

Example 200N-{[(2-{4-[2-(2-Cyclopenten-1-ylmethyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,formate

[2098] MS (ESI) m/z 544.40 (M+H)⁺.

Example 201N-{[(2-{4-[2-(1-Cyclopenten-1-ylmethyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,formate

[2099] MS (ESI) m/z 544.40 (M+H)⁺.

Example 202(2Z)-3-[5,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-propyl-2-propenamide,formate

[2100] MS (ESI) m/z 575.44 (M+H)⁺.

Example 203N-{[(2-{4-[5,7-Dimethyl-2-(1-methyl-3-oxo-3-phenylpropyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,formate

[2101] MS (ESI) mz 610.49 (M+H)⁺.

Example 204N-{[(2-{4-[5,7-Dimethyl-2-(3,3,3-trifluoro-2-methylpropyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,formate

[2102] MS (ESI) m/z 574.43 (M+H)⁺.

Example 205N-({[2-(4-{2-[2-(Diethylamino)ethyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide,formate

[2103] MS (ESI) m/z 563.49 (M+H)⁺.

Example 206N-({[2-(4-{2-[2-(4-Fluorophenyl)ethyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide,formate

[2104] MS (ESI) m/z 586.46 (M+H)⁺.

Example 2073-[5,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N,N-diethylpropanamide,formate

[2105] MS (ESI) m/z 591.50 (M+H)⁺.

Example 208N-[({2-[4-(5,7-Dimethyl-2-tetrahydro-3-furanyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide,formate

[2106] MS (ESI) nlz 534.41 (M+H)⁺.

Example 209N-{[(2-{4-[5,7-Dimethyl-2-(1-methylbutyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,formate

[2107] MS (ESI) m/z 534.45 (M+H)⁺.

Example 210N-{[(2-{4-[2-(Cyclopentylmethyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,formate

[2108] MS (ESI) m/z 546.46 (M+H)⁺.

Example 211N-{[(2-{4-[5,7-Dimethyl-2-(2-methylcyclopropyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,formate

[2109] MS (ESI) m/z 518.41 (M+H)⁺.

Example 212N-[({2-[4-(5,7-Dimethyl-2-{3-[4-(methyloxy)phenyl]-3-oxopropyl}-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide,formate

[2110] MS (ESI) m/z 626.45 (M+H)⁺.

Example 213N-({[2-(4-{2-[3-(3,4-Dimethylphenyl)propyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide,formate

[2111] MS (ESI) m/z 610.28 (M+H)⁺.

Example 214N-({[2-(4-{2-[(Z)-2-(4-Fluorophenyl)ethenyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide,formate

[2112] MS (ESI) m/z 584.41 (M+H)⁺.

Example 215N-[({2-[4-(5,7-Dimethyl-2-{(Z)-2-[2-(methyloxy)phenyl]ethenyl}-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide,formate

[2113] MS (ESI) m/z 596.29 (M+H)⁺.

Example 216N-{[(2-{4-[2-(5-Hexynyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}4-methylbenzenesulfonamide,formate

[2114] MS (ESI) m/z 544.33 (M+H)⁺.

The Synthetic Procedure of Example 217-Example 220

[2115] The compounds disclosed hereinafter were prepared according tothe following procedure: To a solution of3-amino-4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl)anilino)pyridine(0.044 mmol) in dichloromethane (DCM) (0.2 mL) and DMF (0.05 mL) wasadded pyridine (0.103 mmol) in DCM (0.2 mL), and excess of acid chloride(0.066 mmol-0.088 mmol) at room temperature. The reaction mixture wasstirred at ambient temperature until the starting compound wasdisappeared (4-6 hr). After the reaction was stopped, to the reactionmixture was added MeOH (0.2 mL), then stirred for 1 hr. The solvent wasremoved by vacuum centrifuge.

[2116] The residue, which was dissolved with MeOH (0.8 mL), was loadedonto a Varian BondElute® SCX cartridge (500 mg/3 mL) which waspreconditioned with 2 mL of MeOH. The solid-phase matrix was washed with5 mL of MeOH and then eluted with 2N ammonia/MeOH (3 mL). The eluate wasconcentrated in vacuo to provide the intermediate product.

[2117] The intermediate product of 1^(st) step was dissolved with EtOH(2 mL), then to the reaction solution was added excess 2N aq.NaOH (1mL). The reaction mixture was stirred at 70° C. over night. After theremoval of solvent, to the residue was added 2N aq.HCl to neutralize.The aqueous layer was extracted with DCM (1 mL×5 times). The organiclayer was dried with sodium sulfate, then concentrated. The crudeproduct was purified by preparative LC/MS (Shiseido capcellpack UG 80C18 (20×50 mm) eluting with MeOH/0.1% HCOOH (v/v, 20/80 to 90/10) togive the title compound as a formate.

Example 2174-Methyl-N-[({2-[4-(2,5,7-trimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]benzenesulfonamide,formate

[2118] MS (ESI) m/z 478.31 (M+H)⁺.

Example 218N-{[(2-{4-[2-(2,2-Dimethylpropyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,formate

[2119] MS (ESI) m/z 534.40 (M+H)⁺.

Example 219N-[({2-[4-(2-Cyclobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide,formate

[2120] MS (ESI) m/z 518.38 (M+H)⁺.

Example 220N-[({2-[4-(2-Cyclopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide,formate

[2121] MS (ESI) m/z 532.44 (M+H)⁺.

Example 2214-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl(4-methylphenyl)sulfonylcarbamatep-toluenesulfonate

[2122] A mixture of4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl(4-methylphenyl)sulfonylcarbamate(Example 106, 150 mg, 0.265 mmol), p-toluenesulfonic acid (50.5 mg,0.265 mmol) in acetone (3% H₂O, 0.3 ml) was stirred at room temperaturefor 16 h. The precipitated crystalline solids were filtered, washed withacetone (0.05 ml×5), and dried in vacuo at 40° C. for 2 h to afford 158mg (81%) of the title compound as white solids.

[2123] m.p.: 234.8° C.

[2124]¹H-NMR (CDCl₃) δ: 8.66 (1H, br.s), 8.35 (1H, s), 7.85 (2H, d,J=8.1 Hz), 7.81 (2H, d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz), 7.39-7.35(3H, m), 7.29 (2H, d, J=7.9 Hz), 7.19 (2H, d, J=7.9 Hz), 4.35 (2H, t,J=6.2 Hz), 3.13 (2H, q, J=7.6 Hz), 3.04 (2H, t, J=6.3 Hz), 2.42 (3H, s),2.36 (3H, s), 1.43 (3H, t, J=7.4 Hz).

Example 2224-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl(4-methylphenyl)sulfonylcarbamatebenzenesulfonate

[2125] The title compound was prepared according to the proceduredescribed in Example 221 from4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl(4-methylphenyl)sulfonylcarbamate(Example 106).

[2126] m.p.: 194.9° C.

[2127]¹H-NMR (CDCl₃) δ: 8.83 (1H, br.s), 8.39 (1H, s), 7.99-7.95 (2H,m), 7.81 (2H, d, J=8.4 Hz), 7.54 (2H, d, J=8.4 Hz), 7.41-7.36 (6H, m),7.29 (2H, d, J=8.4 Hz), 4.34 (2H, t, J=6.1 Hz), 3.14 (2H, q, J=7.6 Hz),3.03 (2H, t, J=6.1 Hz), 2.41 (3H, s), 1.42 (3H, t, J=7.4 Hz).

Example 2234-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl(4-methylphenyl)sulfonylcarbamatemethanesulfonate

[2128] The title compound was prepared according to the proceduredescribed in Example 221 from4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl(4-methylphenyl)sulfonylcarbamate(Example 106).

[2129] m.p.: 172.2° C.

[2130]¹H-NMR (CDCl₃) δ: 9.03 (1H, br.s), 8.52 (1H, s), 7.81 (2H, d,J=8.2 Hz), 7.56 (2H, d, J=8.2 Hz), 7.40 (2H, d, J=8.1 Hz), 7.39 (1H, s),7.29 (2H, d, J=8.1 Hz), 4.35 (2H, t, J=6.3 Hz), 3.16 (2H, q, J=7.6 Hz),3.06 (2H, t, J=6.3 Hz), 2.94 (3H, s), 2.41 (3H, s), 1.45 (3H, t, J=7.6Hz).

Example 2245-Acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazolep-toluenesulfonate

[2131] A mixture of5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole(Example 78, 43 mg, 0.085 mmol), p-toluenesulfonic acid (16.2 mg, 0.085mmol) in ethanol (0.1 ml) was stirred at room temperature for 16 h. Theprecipitated crystalline solids were filtered, washed with ethanol (0.05ml×5), and dried in vacuo at 40° C. for 2 h to afford 54 mg (91%) of thetitle compound as white solids.

[2132] m.p.: 166.7° C.

[2133]¹H-NMR (CDCl₃) δ: 9.85 (1H, br.s), 8.50 (1H, s), 8.02 (1H, d,J=8.9 Hz), 7.86 (2H, d, J=8.1 Hz), 7.68 (2H, dd, J=1.8, 8.2 Hz), 7.47(2H, d, J=8.4 Hz), 7.36-7.31 (3H, m), 7.22 (2H, d, J=8.4 Hz), 7.17 (2H,d, J=8.4 Hz), 7.00 (1H, br.s), 3.47-3.39 (2H, m) 3.14 (2H, q, J=7.3 Hz),2.88 (2H, t, J=6.3 Hz), 2.58 (3H, s), 2.35 (3H, s), 2.34 (3H, s), 1.45(3H, t, J=7.6 Hz).

Example 2255-Acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazolebenzenesulfonate

[2134] The title compound was prepared according to the proceduredescribed in Example 224 from5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole(Example78).

[2135] m.p.: 117.7° C.

[2136]¹H-NMR (CDCl₃) δ: 9.62 (1H, br.s), 8.52 (1H, s), 8.05-7.96 (3H,m), 7.67 (2H, d, J=8.2 Hz), 7.49-7.43 (5H, m), 7.37-7.32 (3H, m), 7.19(2H, d, J=8.2 Hz), 6.92-6.88 (1H, m), 3.48-3.42 (2H, m) 3.17 (2H, q,J=7.6 Hz), 2.89 (2H, t, J=6.1 Hz), 2.61 (3H, s), 2.35 (3H, s), 1.49 (3H,t, J=7.6 Hz).

Example 226 4-Chloro-2-ethyl-6-methyl-1-(4-12-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine

[2137] Step 1. tert-Butyl2-{4-[(2-chloro-6-methyl-3-nitro-4-pyridinyl)amino]phenyl}ethylcarbamate

[2138] A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine (Chorvat,Robert J. et al., J.Med.Chem., 1999, 42, 833., 7.5 g, 36.2 mmol),[2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (Stark, PeterA. et al., J.Med.Chem., 1992, 35, 4264., 1.14 g, 4.83 mmol) inN,N-diisopropylethylamine (50 ml) was heated at reflux temperature for16 h. After cooling, the mixture was concentrated. The residue wasdiluted with dichloromethane (200 ml) and washed with saturated aqueousNaHCO₃ solution (50 ml×2). The organic layer was dried (MgSO₄), andconcentrated. Purification by flash column chromatography eluting withhexane/ethyl acetate (1:1) to afford 310 mg (16%) of the title compoundas orange solids.

[2139]¹H-NMR (CDCl₃) δ: 8.19 (1H, s), 7.28 (2H, d, J=8.4 Hz), 7.16 (2H,d, J=8.3 Hz), 6.69 (1H, s), 4.62 (1H, br s), 3.43-3.37 (2H, m), 2.84(2H, t, J=7.0 Hz), 2.37 (3H, s), 1.44 (9H, s).

[2140] Step 2. tert-Butyl2-{4-[(3-amino-2-chloro-6-methyl-4-pyridinyl)amino]phenyl}ethylcarbamate

[2141] The title compound was prepared according to the proceduredescribed in step 1 of Example 6 from tert-butyl2-{4-[(2-chloro-6-methyl-3-nitro-4-pyridinyl)amino]phenyl}ethylcarbamate(step 1).

[2142]¹H-NMR (CDCl₃) δ: 7.18 (2H, d, J=8.3 Hz), 7.03 (2H, d, J=8.2 Hz),6.76 (1H, s), 6.02 (1H, br. s), 4.61 (1H, br. s), 3.40-3.37 (4H, m),2.78 (2H, t, J=7.0 Hz), 2.33 (3H, s), 1.44 (9H, s).

[2143] Step 3. tert-Butyl2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylcarbamate

[2144] A mixture of tert-butyl2-{4-[(3-amino-2-chloro-6-methyl-4-pyridinyl)amino]phenyl]ethylcarbamate(step 2, 238 mg, 0.63 mmol), propionyl chloride (70 mg, 0.76 mmol) intoluene (4.6 ml) and dichloromethane (0.6 ml) was heated at refluxtemperature for 1 h. After cooling, the mixture was diluted with ethylacetate (100 ml) and washed with IN aqueous NaOH solution (30 ml×2) andbrine (30 ml). The organic layer was dried (MgSO₄), and concentrated.The residue and p-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) intoluene (5.0 ml) was heated at reflux temperature for 16 h. Aftercooling, the mixture was diluted with dichloromethane (100 ml) andwashed with saturated aqueous NaHCO₃ solution (30 ml) and brine (30 ml).The organic layer was dried (MgSO₄), and concentrated. Purification byPTLC eluting with hexane/ethyl acetate (1:1) to afford 90 mg (34%) ofthe title compound as a brown oil.

[2145]¹H-NMR (CDCl₃) δ: 7.44 (2H, d, J=8.2 Hz), 7.27 (2H, d, J=8.2 Hz),6.81 (1H, s), 4.75 (1H, br s), 3.52-3.44 (2H, m), 2.94 (2H, t, J=7.1Hz), 2.82 (2H, q, J=7.6 Hz), 2.55 (3H, s), 1.46 (9H, s), 1.32 (3H, t,J=7.6 Hz).

[2146] Step 4.2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanamine

[2147] To a stirred solution of tert-butyl2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylcarbamate(step 3, 90 mg, 0.22 mmol) in dichloromethane (8.5 ml) was addedtrifluoroacetic acid (1.0 ml, 13.0 mmol) at 0° C., and the mixture wasstirred at 0° C. for 30 min, then at room temperature for 5 h. Themixture was concentrated, and diluted with dichloromethane (50 ml),washed with saturated aqueous NaHCO₃ solution (10 ml) and brine (10 ml).The organic layer was dried (MgSO₄), and concentrated. Purification byPTLC eluting with ethyl acetate to afford 50 mg (73%) of the titlecompound as a brown oil.

[2148]¹H-NMR (CDCl₃) δ: 7.45 (2H, d, J=8.2 Hz), 7.27 (2H, d, J=8.2 Hz),6.81 (1H, s), 3.09 (2H, t, J=6.9 Hz), 2.89 (2H, t, J=6.8 Hz), 2.83 (2H,q, J=7.4 Hz), 2.55 (3H, s), 1.31 (3H, t, J=7.4 Hz).

[2149] Step 5.4-chloro-2-ethyl-6-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)aminolethyl}phenyl)-1H-imidazo[4,5-c]pyridine

[2150] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanamine(step 4).

[2151] m.p.: 163° C.

[2152] MS (ESI) m/z: 512 [(MH)⁺], 510 [(M−H)⁻].

[2153]¹H-NMR (CDCl₃) δ: 7.73 (2H, d, J=8.2 Hz), 7.38-7.21 (6H, m), 6.78(1H, s), 3.53-3.51 (2H, m), 2.91-2.89 (2H, m), 2.79 (2H, q, J=7.2 Hz),2.52 (3H, s), 2.37 (3H, s), 1.29 (3H, t, J=7.2 Hz).

Example 2272-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[2154] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol(step 4 of Example 42).

[2155] m.p.: 158° C.

[2156] MS (ESI) m/z: 493 [(MH)⁺], 491 [(M−H)⁻].

[2157]¹H-NMR (DMSO-d₆) δ: 7.72 (2H, d, J=8.2 Hz), 7.47 (2H, d, J=8.6Hz), 7.43 (2H, d, J=8.6 Hz), 7.34 (2H, d, J=8.0 Hz), 6.96 (1H, s), 4.18(2H, t, J=6.6 Hz), 2.94 (2H, t, J=6.4 Hz), 2.76 (3H, s), 2.74 (2H, q,J=7.3 Hz), 2.50 (3H, s), 2.35 (3H, s), 1.23 (3H, t, J=7.3 Hz).

Example 228 2-[4-(8-Ethyl-2,6-dimethyl-9H-purin-9-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[2158] Step 1.2-{4-[(6-chloro-2-methyl-5-nitro-4-pyrimidinyl)aminolphenyl}ethanol

[2159] To a stirred solution of 4,6-dichloro-2-methyl-5-nitro-pyrimidine(Albert et al., J.Chem.Soc., 1954, 3832, 7.5 g, 36.1 mmol) in THF (150ml) was added 4-aminophenylethyl alcohol (2.47 g, 18.0 mmol),triethylamine (3.65 g, 36.1 mmol), and the mixture was stirred at roomtemperature for 1 h. The reaction was quenched with water (10 ml), andthe mixture was extracted with ethyl acetate (100 ml×3). The organiclayer was washed with brine (50 ml), dried (MgSO₄), and concentrated.Purification by flash column chromatography eluting with hexane/ethylacetate (gradient elution from 1:1 to 1:2) to afford 4.0 g (72%) of thetitle compound as a yellow solid.

[2160]¹H-NMR (CDCl₃) δ: 9.34 (1H, s), 7.50 (2H, d, J=8.4 Hz), 7.28 (2H,d, J=8.8 Hz), 3.89 (2H, t, J=6.6 Hz), 2.90 (2H, t, J=6.4 Hz), 2.57 (3H,s).

[2161] Step 2. diethyl2-(6-{[4-(2-Hydroxyethyl)phenyl]amino}-2-methyl-5-nitro-4-pyrimidinyl)propanedioate

[2162] To a stirred solution of2-{4-[(6-chloro-2-methyl-5-nitro-4-pyrimidinyl)amino]phenyl}ethanol(step 1, 2.0 g, 6.48 mmol) in acetone (61 ml) was added diethyl malonate(1.53 g, 9.54 mmol) at 0° C., then aqueous NaOH solution (11N, 2 ml, 22mmol) was added dropwise over 20 min. After addition, the mixture wasstirred at room temperature for 1 h. The reaction was quenched withwater (120 ml), and the pH value was adjusted to 8.0 by addition ofacetic acid. The whole was extracted with ethyl acetate (100 ml×3). Theorganic layer was washed with brine (50 ml), dried (MgSO₄), andconcentrated. Removal of excess diethyl malonate by azetropicaldistilation with toluene afforded 3.26 g (72%) of the title compound asa brown oil.

[2163] MS (EI) m/z: 432 (M⁺).

[2164]¹H-NMR (CDCl₃) δ: 10.15 (1H, s), 7.55 (2H, d, J=8.4 Hz), 7.27 (2H,d, J=8.4 Hz), 5.36 (1H, s), 4.31 (4H, q, J=7.1 Hz), 3.90 (2H, t, J=6.6Hz), 2.90 (2H, t, J=6.4 Hz), 2.56 (3H, s), 1.32 (6H, t, J=7.1 Hz).

[2165] Step 3.2-{4-[(2,6-dimethyl-5-nitro-4-pyrimidinyl)amino]phenyl}ethanol

[2166] A mixture of diethyl2-(6-{[4-(2-hydroxyethyl)phenyl]amino}-2-methyl-5-nitro-4-pyrimidinyl)propanedioate(step 2, 2.0 g, 6.48 mmol) in 2N aqueous HCl (15 ml) was heated atreflux temperature for 5 h. After cooling, the reaction was quenchedwith saturated NaHCO₃ aqueous solution (100 ml), and the whole wasextracted with ethyl acetate (100 ml×3). The organic layer was washedwith brine (50 ml), dried (MgSO₄), and concentrated. Purification byflash column chromatography eluting with hexane/ethyl acetate (gradientelution from 1:1 to 0:100) to afford 1.33 g (71%) of the title compoundas a yellow solid.

[2167] MS (EI) m/z: 288 (M⁺).

[2168]¹H-NMR (CDCl₃) δ: 9.81 (1H, s), 7.56 (2H, d, J=8.4 Hz), 7.27 (2H,d, J=8.4 Hz), 3.92-3.86 (2H, m), 2.89 (2H, t, J=6.4 Hz), 2.76 (3H, s),2.56 (3H, s).

[2169] Step 4.2-{4-[(5-amino-2,6-dimethyl-4-pyrimidinyl)amino]phenyl}ethanol

[2170] The title compound was prepared according to the proceduredescribed in step 1 of Example 6 from2-{4-[(2,6-dimethyl-5-nitro-4-pyrimidinyl)amino]phenyl}ethanol (step 3).

[2171] MS (EI) m/z: 258 (M⁺).

[2172]¹H-NMR (DMSO-d₆) δ: 8.14 (1H, s), 7.63 (2H, d, J=8.6 Hz), 7.12(2H, d, J=8.4 Hz), 4.67 (2H, br.s), 3.58 (2H, t, J=7.3 Hz), 2.67 (2H, t,J=7.2 Hz), 2.28 (3H, s), 2.20 (3H, s).

[2173] Step 5. 2-[4-(8-ethyl-2,6-dimethyl-9H-purin-9-yl)phenyl]ethylpropanoate

[2174] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(5-amino-2,6-dimethyl-4-pyrimidinyl)amino]phenyl}ethanol (step 4).

[2175]¹H-NMR (CDCl₃) δ: 7.44 (2H, d, J=8.2 Hz), 7.31 (2H, d, J=8.2 Hz),4.37 (2H, t, J=6.9 Hz), 3.06 (2H, t, J=6.8 Hz), 2.84 (3H, s), 2.82 (2H,q, J=7.4 Hz), 2.70 (3H, s), 2.35 (2H, q, J=7.6 Hz), 1.31 (3H, t, J=7.6Hz), 1.15 (3H, t, J=7.6 Hz).

[2176] Step 6. 2-[4-(8-ethyl-2,6-dimethyl-9H-purin-9-yl)phenyl]ethanol

[2177] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(8-ethyl-2,6-dimethyl-9H-purin-9-yl)phenyl]ethyl propanoate (step5).

[2178]¹H-NMR (CDCl₃) δ: 7.46 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.3 Hz),3.99-3.92 (2H, m), 2.99 (2H, t, J=6.4 Hz), 2.85 (3H, s), 2.83 (2H, q,J=7.5 Hz), 2.70 (3H, s), 1.32 (3H, t, J=7.3 Hz).

[2179] Step 7. 2-[4-(8-ethyl-2,6-dimethyl-9H-purin-9-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[2180] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(8-ethyl-2,6-dimethyl-9H-purin-9-yl)phenyl]ethanol (step 6).

[2181] m.p.: 162° C.

[2182] MS (ESI) m/z: 494 [(MH)⁺], 492 [(M−H)⁻].

[2183]¹H-NMR (CDCl₃) δ: 7.94 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.1 Hz),7.24 (2H, d, J=8.6 Hz), 7.18 (2H, d J=8.4 Hz), 4.36 (2H, t, J=6.4 Hz),2.97 (2H, t, J=6.2 Hz), 2.86 (3H, s), 2.79 (2H, q, J=7.6 Hz), 2.64 (3H,s), 2.44 (3H, s),1.28 (3H, t, J=7.6 Hz).

Example 2292-[4-(4,6-Dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[2184] Step 1.2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylbenzoate

[2185] A mixture of2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2 ofExample 42, 500 mg, 1.94 mmol), benzoic acid (4.45 g 36.4 mmol), benzoicanhydride (4.8 g, 21.2 mmol) was heated at 120° C. for 4 h. Aftercooling, the mixture was diluted with dichloromethane (100 ml). Thesolution was washed with saturated NaHCO₃ aqueous solution (50 ml),brine (50 ml), dried (MgSO₄), and concentrated. Purification by flashcolumn chromatography eluting with ethyl acetate to afford 813 mg (94%)of the title compound as a white solid.

[2186] MS (EI) m/z: 447(M⁺).

[2187]¹H-NMR (CDCl₃) δ: 8.02-7.21 (14H, m), 6.87 (1H, s), 4.61 (2H, t,J=7.0 Hz), 3.18 (2H, t, J=6.8 Hz), 2.96 (3H, s), 2.61 (3H, s).

[2188] Step 2.2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol

[2189] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylbenzoate (step 1).

[2190]¹H-NMR (CDCl₃) δ: 7.57-7.18 (9H, m), 6.87 (1H, s), 3.95 (2H, t,J=6.6 Hz), 2.96 (2H, t, J=6.6 Hz), 2.94 (3H, s), 2.59 (3H, s).

[2191] Step 3.2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[2192] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol(step 2).

[2193] m.p.: 194° C.

[2194] MS (ESI) m/z: 541 [(MH)⁺], 539 [(M−H)⁻].

[2195]¹H-NMR (CDCl₃) δ: 7.89 (2H, d, J=8.2 Hz), 7.46-6.95 (11H, m), 6.77(1H, s), 4.35 (2H, t, J=6.0 Hz), 3.03 (3H, s), 2.96 (2H, t, J=6.0 Hz),2.56 (3H, s), 2.42 (3H, s).

Example 2302-[4-(2-Butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[2196] Step 1.2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylpentanoate

[2197] The title compound was prepared according to the proceduredescribed in step 1 of Example 229 from2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2 ofExample 42).

[2198]¹H-NMR (CDCl₃) δ: 7.44 (2H, d, J=8.1 Hz), 7.26 (2H, d, J=8.2 Hz),6.71 (1H, s), 4.38 (2H, t, J=6.9 Hz), 3.07 (2H, t, J=6.9 Hz), 2.88 (3H,s), 2.78 (2H, t, J=7.6 Hz), 2.56 (3H, s), 2.33 (2H, t, J=7.4 Hz),1.74-1.55 (4H, m), 1.41-1.24 (4H, m), 0.91 (3H, t, J=7.2 Hz), 0.84 (3H,t, J=7.2 Hz).

[2199] Step 2.2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol

[2200] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylpentanoate (step 1).

[2201]¹H-NMR (CDCl₃) δ: 7.46 (2H, d, J=8.2 Hz), 7.25 (2H, d, J=8.2 Hz),6.72 (1H, s), 4.00 (2H, t, J=6.6 Hz), 3.02 (2H, t, J=6.4 Hz), 2.88 (3H,s), 2.78 (2H, t, J=7.6 Hz), 2.54 (3H, s), 1.76-1.64 (2H, m), 1.39-1.25(2H, m), 0.85 (3H, t, J=7.4 Hz).

[2202] Step 3.2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[2203] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol(step 2).

[2204] m.p.: 162° C.

[2205] MS (ESI) m/z: 521 [(MH)⁺], 519 [(M−H)⁻].

[2206]¹H-NMR (CD₃OD) δ: 7.97 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=7.9 Hz),7.18 (2H, d, J=8.4 Hz), 6.84 (2H, d, J=8.4 Hz), 6.60 (1H, s), 4.34 (2H,t, J=5.5 Hz), 3.03 (3H, s), 2.96 (2H, t, J=5.5 Hz), 2.71 (2H, t, J=7.5Hz), 2.52 (3H, s), 2.43 (3H, s), 2.43 (3H, s), 1.72-1.62 (2H, m),1.36-1.24 (2H, m), 0.84 (3H, t, J=7.3 Hz).

Example 2312-[4-(2-Butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate p-toluenesulfonate

[2207] To a solution of2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate (Example 230) in methanol was addedTsOH (1.0 eq.). The resulting mixture was stirred at room temperaturefor 5 min and concentrated. The residual solids were collected and driedunder reduced pressure at 50° C. to afford the title compound as whitesolids:

[2208]¹H-NMR (CDCl₃) δ: 7.89-7.86 (4H, m), 7.49 (2H, d, J=8.3 Hz), 7.30(2H, d, J=8.1 Hz), 7.24 (2H, d, J=8.3 Hz), 7.18 (2H, d, J=7.9 Hz), 7.03(1H, s), 4.34 (2H, t, J=6.2 Hz), 3.12 (3H, s), 3.02 (2H, t, J=6.2 Hz),2.80 (3H, s), 2.77 (2H, t, J=8.1 Hz), 2.42 (3H, s), 2.34 (3H, s),1.78-1.68 (2H, m), 1.39-1.27 (2H, m), 0.86 (3H, t, J=7.3 Hz).

Example 2322-[4-(4,6-Diethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[2209] Step 1.2-{4-[4,6-dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl]ethyl2-methylpropanoate

[2210] The title compound was prepared according to the proceduredescribed in step 1 of Example 229 from2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2 ofExample 42).

[2211]¹H-NMR (CDCl₃) δ: 7.44 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.4 Hz),6.66 (1H, s), 4.38 (2H, t, J=7.0 Hz), 3.08 (2H, t, J=6.8 Hz), 3.12-3.02(1H, m), 2.89 (3H, s), 2.55 (3H, s), 2.61-2.48 (1H, m), 1.33 (6H, d,J=7.0 Hz), 1.15 (6H, d, J=w.0 Hz).

[2212] Step 2.2-{4-[4,6-dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethanol

[2213] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[4,6-dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl2-methylpropanoate (step 1).

[2214]¹H-NMR (CDCl₃) δ: 7.46 (2H, d, J=8.2 Hz), 7.25 (2H, d, J=8.3 Hz),6.68 (1H, s), 4.00 (2H, t, J=6.6 Hz), 3.13-3.04 (1H, m), 3.02 (2H, t,J=6.6 Hz), 2.88 (3H, s), 2.53 (3H, s), 1.33 (6H, d, J=7.0 Hz).

[2215] Step 3.2-{4-[4,6-dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[2216] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[4,6-dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl]ethanol(step 2).

[2217] m.p.: 213° C.

[2218] MS (ESI) m/z: 507 [(MH)⁺], 505 [(M−H)⁻].

[2219]¹H-NMR (CD₃OD) δ: 7.80 (2H, d, J=8.4 Hz), 7.51 (2H, d, J=8.6 Hz),7.34 (2H, d, J=8.6 Hz), 7.29 (2H, d, J=8.1 Hz), 7.01 (1H, s), 4.26 (2H,t, J=6.6 Hz), 3.15-3.09 (1H, m), 3.00 (2H, t, J=6.4 Hz), 2.90 (3H, s),2.58 (3H, s), 2.36 (3H, s), 1.33 (6H, d, J=6.8 Hz).

Example 2332-{4-[2-(1,1-Dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[2220] Step 1.2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl{ethyl2,2-dimethylpropanoate

[2221] The title compound was prepared according to the proceduredescribed in step 1 of Example 229 from2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2 ofExample 42).

[2222]¹H-NMR (CDCl₃) δ: 7.41 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.4 Hz),6.35 (1H, s), 4.38 (2H, t, J=6.6 Hz), 3.08 (2H, t, J=6.6 Hz), 2.87 (3H,s), 2.50 (3H, s), 1.34 (9H, s), 1.17 (9H, s).

[2223] Step 2.2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethanol

[2224] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl2,2-dimethylpropanoate (step 1).

[2225]¹H-NMR (CDCl₃) δ: 7.42 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.6 Hz),6.38 (1H, s), 4.00 (2H, t, J=6.4 Hz), 3.01 (2H, t, J=6.6 Hz), 2.87 (3H,s), 2.50 (3H, s), 1.34 (9H, s).

[2226] Step 3.2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[2227] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethanol(step 2).

[2228] m.p.: 226° C.

[2229] MS (ESI) m/z: 521 [(MH)⁺], 519 [(M−H)⁻].

[2230]¹H-NMR (DMSO-d₆) δ: 7.71 (2H, d, J=8.3 Hz), 7.46 (2H, d, J=8.6Hz), 7.41 (2H, d, J=8.6 Hz), 7.35 (2H, d, J=8.1Hz), 6.55 (1H, s), 4.20(2H, t, J=7.0 Hz), 2.95 (2H, t, J=7.0 Hz), 2.74 (3H, s), 2.44 (3H, s),2.36 (3H, s), 1.27 (9H, s).

Example 2342-[4-(2-Cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[2231] Step 1.2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylcyclohexanecarboxylate

[2232] The title compound was prepared according to the proceduredescribed in step 1 of Example 229 from2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2 ofExample 42).

[2233]¹H-NMR (CDCl₃) δ: 7.44 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz),6.65 (1H, s), 4.39 (2H, t, J=6.8 Hz), 3.08 (2H, t, J=6.8 Hz), 2.88 (3H,s), 2.54 (3H, s), 2.71-1.21 (22H, m).

[2234] Step 2.2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol

[2235] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylcyclohexanecarboxylate (step 1).

[2236]¹H-NMR (CDCl₃) δ: 7.46 (2H, d, J=8.2 Hz),7.25 (2H, d, J=8.2 Hz),6.68 (1H, s), 4.01 (2H, t, J=6.4 Hz), 3.02 (2H, t, J=6.4 Hz), 2.88 (3H,s), 2.72-2.70 (1H, m), 2.54 (3H, s), 2.30-1.15 (10H, m).

[2237] Step 3.2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methyltphenyl)sulfonylcarbamate

[2238] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol(step 2).

[2239] m.p.: 168° C.

[2240] MS (ESI) m/z: 547 [(MH)⁺], 545 [(M−H)⁻].

[2241]¹H-NMR (CD₃OD) δ: 7.97 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.1 Hz),7.19 (2H, d, J=8.3 Hz), 6.77 (2H, d, J=8.2 Hz), 6.53 (1H, s), 4.33 (2H,t, J=5.3 Hz), 3.09 (3H, s), 2.97 (2H, t, J=5.5 Hz), 2.65-2.55 (1H, m),2.50 (3H, s), 2.42 (3H, s), 1.77-1.18 (10H, m).

Example 2352-{4-[4.6-Dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[2242] Step 1.2-{4-[-4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl4-phenylbutanoate

[2243] The title compound was prepared according to the proceduredescribed in step 1 of Example 229 from2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2 ofExample 42).

[2244]¹H-NMR (CDCl₃) δ: 7.39 (2H, d, J=8.2 Hz), 7.30-7.15 (1OH, m), 7.06(2H, d, J=6.4 Hz), 6.70 (1H, s), 4.37 (2H, t, J=7.1 Hz), 3.06 (2H, t,J=6.9 Hz), 2.88 (3H, s), 2.80 (2H t, J=7.6 Hz), 2.68-2.60 (4H, m), 2.54(3H, s), 2.36 (2H, t, J=7.4 Hz), 2.09-1.91 (4H, m).

[2245] Step 2.2-{4-[-4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethanol

[2246] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[-4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl4-phenylbutanoate (step 1).

[2247]¹H-NMR (CDCl₃) δ: 7.41 (2H, d, J=8.2 Hz), 7.25-7.15 (5H, m), 7.07(2H, d, J=6.8 Hz), 6.72 (1H, s), 3.99 (2H, t, J=6.6 Hz), 3.00 (2H, t,J=6.3 Hz), 2.88 (3H, s), 2.81 (2H, t, J=7.6 Hz), 2.64 (2H, d, J=7.6 Hz),2.55 (3H, s), 2.11-2.00 (2H, m).

[2248] Step 3.2-{4-[-4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[2249] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[-4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethanol(step 2).

[2250] m.p.: 175° C.

[2251] MS (ESI) m/z: 583 [(MH)⁺], 581 [(M−H)⁻].

[2252]¹H-NMR (CDCl₃) δ: 7.95 (2H, d, J=8.3 Hz), 7.30-7.14 (7H, m), 7.03(2H, d, J=8.1 Hz), 6.81 (2H, d, J=8.0 Hz), 6.64 (1H, s), 4.33 (2H, t,J=5.7 Hz), 3.00 (3H, s), 2.95 (2H, t, J=5.7 Hz), 2.72 (2H, t, J=7.5 Hz),2.62 (2H, t, J=7.4 Hz), 2.51 (3H, s), 2.41 (3H, s), 2.07-1.97 (2H, m).

Example 2364-Methyl-N-{[(2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}benzenesulfonamidep-toluenesulfonate

[2253] Step 1.2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethanol

[2254] A mixture of2-(4-{[2-amino-4-(methyloxy)phenyl]amino}phenyl)ethanol (step 2 ofExample 71, 1.95 g, 7.56 mmol), pyrazol-3-carbaldehyde (726 mg, 7.56mmol) in ethanol (45 ml) was heated at reflux temperature for 2 h. Aftercooling, the mixture was concentrated. A mixture of the residue, leadtetraacetate (4.61 g, 8.32 mmol) in benzene (50 ml) was stirred at roomtemperature for 16 h. The mixture was 1.37 mmol) in methanol (4 ml) wasadded 10% HCl in methanol (2 ml) at room extracted with ethyl acetate(150 ml×4). The organic layer was washed with water (100 ml×5), brine(50 ml), dried (MgSO₄), and concentrated. Purification by flash columnchromatography eluting with dichloromethane/methanol (gradient elutionfrom 20:1 to 10:1) to afford 408 mg (16%) of the title compound as anamber solid.

[2255] MS (EI) m/z: 334 (M⁺).

[2256]¹H-NMR (DMSO-d₆) δ: 7.6 (1H, br.s), 7.43 (2H, d, J=7.7 Hz),7.29-7.23 (3H, m), 7.04 (1H, d, J=8.8 Hz), 6.90 (1H, d, J=8.8 Hz), 6.34(1H, br.s), 3.85-3.81 (5H, m), 2.92 (2H, t, J=6.6 Hz).

[2257] Step 2.1-[4-(2-chloroethyl)phenyl]-5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazole

[2258] The title compound was prepared according to the proceduredescribed in step 7 Example 1 from2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 1).

[2259] MS (EI) m/z: 352 (M⁺).

[2260]¹H-NMR (CDCl₃) δ: 8.96 (0.5H, s), 8.11 (0.5H, d, J=2.9 Hz), 7.50(0.5H, d, J=2.0 Hz), 7.46-7.34 (5H, m), 7.05 (1H, dd, J=16.5, 8.8 Hz),6.93 (1H, ddd, J=1.4, 9.0, 2.4 Hz), 6.71 (0.5H, dd, J=2.9, 1.1 Hz), 5.81(1H, s), 3.85 (3H, s), 3.82 (2H, t, J=7.0 Hz), 3.22 (2H, t, J=7.0 Hz).

[2261] Step 3.1-[4-(2-azidoethyl)phenyl]-5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazole

[2262] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from1-[4-(2-chloroethyl)phenyl]-5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazole(step 2).

[2263] MS (EI) m/z: 359 (M⁺).

[2264]¹H-NMR (CDCl₃) δ: 14.05 (1H, br.s), 7.53-7.50 (2H, m), 7.45 (2H,d, J=8.4 Hz), 7.37 (2H, d, J=8.4 Hz), 7.01 (1H, d, J=8.7 Hz), 6.89 (1H,dd, J=8.7, 2.4 Hz), 5.81 (1H, s), 3.85 (3H, s), 3.61 (2H, t, J=6.9 Hz),3.03 (2H, t, J=6.9 Hz).

[2265] Step 4.2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethylamine

[2266] The title compound was prepared according to the proceduredescribed in step 9 Example 1 from1-[4-(2-azidoethyl)phenyl]-5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazole(step 3).

[2267] MS (EI) m/z: 333 (M⁺).

[2268]¹H-NMR (CDCl₃) δ: 7.47 (1H, d, J=2.0 Hz), 7.43-7.29 (5H, m), 7.00(1H, d, J=8.8 Hz), 6.88 (1H, dd, J=9.0, 2.4 Hz), 5.81 (1H, s), 3.80 (3H,s), 3.09 (2H, t, J=7.1 Hz), 2.90 (2H, t, J=6.8 Hz).

[2269] Step 5.4-methyl-N-{[(2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl)amin]carbonyl}benzenesulfonamide

[2270] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethylamine(step 4).

[2271] MS (ESI) m/z: 531 [(MH)⁺], 529 [(M−H)⁻].

[2272]¹H-NMR (CDCl₃) δ: 7.77 (2H, d, J=8.3 Hz), 7.44 (1H, s), 7.24 (2H,d, J=7.5 Hz), 7.14-7.07 (5H, m), 6.98 (1H, d, J=9.0 Hz), 6.88 (1H, d,J=9.0 Hz), 6.10 (1H, s), 3.83 (3H, s), 3.57-3.55 (2H, m), 2.88-2.84 (2H,m), 2.35 (3H, s).

[2273] Step 6.4-methyl-N-{[(2-{4-[5-(methyloxy)-2-(1H-p)razol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}benzenesulfonamidep-toluenesulfonamide mono-p-toluenesulfonate

[2274] The title compound was prepared according to the proceduredescribed in Example 231 from4-methyl-N-{[(2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}benzenesulfonamide(step 5).

[2275]¹H-NMR (CDCl₃) δ: 12.65 (1H, s), 9.99 (1H, s), 7.87 (2H, d, J=8.1Hz), 7.78 (2H, d, J=8.3 Hz), 7.50 (2H, d, J=9.0 Hz), 7.39 (2H, d, J=8.4Hz), 7.20 (2H, d, J=7.9 Hz), 7.18 (2H, d, J=8.1 Hz), 7.08-6.93 (5H, m),6.44 (1H, s), 3.76 (3H, s), 3.42-3.40 (2H, m), 2.92-2.88 (2H, m), 2.86(6H, s).

Example 2372-{4-[5-Methyloxy-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate P-toluenesulfonate

[2276] Step 1.2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[2277] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[5-(methoxy)-2-(1H-pyrazol-3yl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 1 of Example 236).

[2278] MS (ESI) m/z: 532 [(MH)⁺], 530 [(M−H)⁻].

[2279]¹H-NMR (DMSO-d₆) δ: 7.75 (2H, d, J=8.1 Hz), 7.58 (2H, d, J=8.1Hz), 7.38 (2H, d, J=7.8 Hz), 7.33-7.21 (3H, m), 7.22 (2H, d, J=8.1 Hz),6.96 (1H, d, J=8.1 Hz), 6.88 (1H, d, J=8.1 Hz), 4.26-4.24 (2H, m), 3.82(3H, s), 2.95-2.93 (2H, m), 2.34 (3H, s).

[2280] Step 2.2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate mono-p-toluenesulfonate

[2281] The title compound was prepared according to the proceduredescribed in Example 231 from2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate (step 1).

[2282]¹H-NMR (CDCl₃) δ: 7.88 (2H, d, J=8.2 Hz), 7.80-7.65 (6H, m), 7.44(2H, d, J=8.1 Hz), 7.38-7.26 (3H, m), 7.17 (2H, d, J=8.1 Hz), 7.10 (2H,d, J=7.6 Hz), 4.37-4.33 (2H, m), 3.03-2.99 (2H, m), 2.39 (3H, s), 2.35(3H, s), 2.31 (3H, s).

Example 2382-{4-[6-Chloro-2-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benimidazol-1-yl]phenyl}ethyl(4-metylphenyl)sulfonylcarbamate

[2283] Step 1.2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate

[2284] To a stirred solution of2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol(step 2 of Example 104, 1.0 g, 2.77 mmol) in dichloromethane (45 ml) wasadded p-toluenesulfonyl isocyanate (574 mg, 2.91 mmol), and the mixturewas stirred at room temperature for 2 h. The mixture was quenched withwater (100 ml). The organic layer was separated. The aqueous layer wasextracted with dichloromethane (100 ml×3). The combined organic layerwas washed with brine (50 ml), dried (MgSO₄), and concentrated.Purification by flash column chromatography eluting with hexane/ethylacetate (gradient elution from 2:1 to 1:1) to afford 1.51 g (98%) of thetitle compound as an orange solid.

[2285]¹H-NMR (CDCl₃) δ: 9.68 (1H, s), 8.58 (1H, s), 7.91 (2H, d, J=8.4Hz), 7.34 (2H, d, J=7.9 Hz), 7.27 (2H, d, J=7.9 Hz), 7.20 (2H, d, J=8.4Hz), 7.17 (1H, s), 4.33 (2H, t, J=7.0 Hz), 2.96 (2H, t, J=6.8 Hz), 2.45(3H, s).

[2286] Step 2.2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate

[2287] To a stirred solution of2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate (step 1, 1.51 g, 2.71 mmol) inmethanol (250 ml) was added 5% platinum-sulfided on carbon (600 mg). Themixture was stirred at room temperature for 5 h under hydrogenatmosphere (4 atm). The palladium catalyst was removed by filtration andwashed with dichloromethane (100 ml). The filtrate was concentratedunder reduced pressure to afford 1.46 g (99%) of the title compound as abrown oil.

[2288]¹H-NMR (CDCl₃) δ: 7.90 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.2 Hz),7.16 (1H, s), 7.07 (2H, d, J=8.2 Hz), 7.06 (1H, s), 6.86 (2H, d, J=8.2Hz), 5.40 (2H, s), 4.26 (2H, t, J=6.9 Hz), 2.85 (2H, t, J=7.2 Hz), 2.44(3H, s).

[2289] Step 3.2-(4-{[5-chloro-2-{[(15-dimethyl-1H-pyrazol-3-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate

[2290] To a stirred solution of2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl])amino}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate (step 2, 200 mg, 0.379 mmol) indichloromethane (1.7 ml) was added a solution of1,5-dimethyl-1H-pyrazole-3-carboxylic acid (63.8 mg, 0.455 mmol) andN,N-diisoprppylethylamine (118 mg, 0.909 mmol) in dichloromethane (1.7ml), then to the mixture was added a solution of HOBt (61.5 mg, 0.455mmol) and HBTU (431 mg, 1.14 mmol) in DMF (2.5 ml), and the mixture wasstirred at room temperature for 20 h. The mixture was quenched withwater (100 ml). The whole was extracted with ethyl acetate (100 ml×3).The combined organic layer was washed with water (100 ml ×3), brine (50ml), dried (MgSO₄), and concentrated. Purification by PTLC eluting withhexane/ethyl acetate (1:1) to afford 145 mg (59%) of the title compoundas a red solid.

[2291]¹H-NMR (CDCl₃) δ: 8.70 (1H, s), 7.87 (2H, d, J=8.1 Hz), 7.79 (1H,s), 7.28 (2H, d, J=8.1 Hz), 7.04 (2H, d, J=8.3 Hz), 6.95 (2H, d, J=8.3Hz), 6.72 (1H, s), 6.60 (1H, s), 4.22 (2H, t, J=6.8 Hz), 3.78 (3H, s),2.84-2.80 (2H, m), 2.40 (3H, s), 2.30 (3H, s).

[2292] Step 4.2-{4-[6-chloro-2-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[2293] A mixture of2-(4-{[5-chloro-2-{[(1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate (step 3, 145 mg, 0.223 mmol) in 2NNaOH (1 ml) and ethanol (2 ml) was stirred at 50° C. for 85 h. Aftercooling, the pH value was adjusted to 4.0 by addition of 2N HCl. Themixture was diluted with water (80 ml), and extracted withdichloromethane (80 ml×3). The combined organic layer was washed withbrine (50 ml), dried (MgSO₄), and concentrated. Purification by PTLCeluting with hexane/ethyl acetate (1:3) to afford 30 mg (21%) of thetitle compound as a red solid.

[2294] MS (ESI) m/z: 632 [(MH)⁺], 630 [(M−H)⁻].

[2295]¹H-NMR (CDCl₃) δ: 8.15 (1H, s), 7.90 (2H, d, J=8.4 Hz), 7.34-7.24(6H, m), 7.19 (1H, s), 5.81 (1H, s), 4.40 (2H, t, J=6.8 Hz), 3.76 (3H,s), 3.04 (2H, t, J=6.4 Hz), 2.41 (3H, s), 2.20 (3H, s).

Example 239N-[({2-[4-(2-Butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

[2296] Step 1.2-butyl-1-[4-(2-chloroethyl)phenyl]-4,6-dimethyl-1H-imidazo[4,5-c]pyridine

[2297] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol(step 2 of Example 230).

[2298] MS (EI) m/z: 341 (M⁺).

[2299]¹H-NMR (CDCl₃) δ: 7.45 (2H, d, J=8.2 Hz), 7.28 (2H, d, J=8.2 Hz),6.73 (1H, s), 3.82 (2H, t, J=7.1 Hz), 3.22 (2H, t, J=7.1 Hz), 2.89 (3H,s), 2.79 (2H, t, J=8.2 Hz), 2.58 (3H, s), 1.76-1.64 (2H, m), 1.39-1.25(2H, m), 0.84 (3H, t, J=7.2 Hz).

[2300] Step2.1-[4-(2-azidoethyl)phenyl]-2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine

[2301] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from2-butyl-1-[4-(2-chloroethyl)phenyl]-4,6-dimethyl-1H-imidazo[4,5-c]pyridine(step 1).

[2302] MS (EI) m/z: 348 (M⁺).

[2303]¹H-NMR (CDCl₃) δ: 7.46 (2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.6 Hz),6.72 (11H, s), 3.62 (2H, t, J=6.8 Hz), 3.03 (2H, t, J=6.8 Hz), 2.88 (3H,s), 2.78 (2H, t, J=7.6 Hz), 2.55 (3H, s), 1.74-1.63 (2H, m), 1.38-1.24(2H, m), 0.84 (3H, t, J=7.3 Hz).

[2304] Step 3.2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylamine

[2305] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from1-[4-(2-azidoethyl)phenyl]-2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine(step 2).

[2306] MS (EI) m/z: 322 (M⁺).

[2307]¹H-NMR (CDCl₃) δ: 7.43 (2H, d, J=8.3 Hz), 7.26 (2H, d, J=8.1 Hz),6.72 (11H, s), 3.10-3.04 (2H, m), 2.90-2.86 (5H, m), 2.78 (2H, t, J=7.7Hz), 2.55 (3H, s), 1.74-1.64 (2H, m), 1.35-1.25 (2H, m), 0.84 (3H, t,J=7.3 Hz).

[2308] Step 4.N-[({2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

[2309] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylamine(step 3).

[2310] MS (ESI) m/z: 520 [(MH)⁺], 518 [(M−H)⁻].

[2311]¹H-NMR (CDCl₃) δ: 7.77 (2H, d, J=8.1 Hz), 7.37 (2H, d, J=7.9 Hz),7.27 (2H, d, J=7.8 Hz), 7.19 (2H, d, J=7.5 Hz), 6.76 (1H, s), 3.57-3.51(2H, m), 2.92 (2H, t, J=6.6 Hz), 2.88 (3H, s), 2.76 (2H, t, J=7.5 Hz),2.52 (3H, s), 2.38 (3H, s), 1.73-1.62 (2H, m), 1.36-1.23 (2H, m), 0.82(3H, t, J=7.3 Hz).

[2312] Step 5.N-[(2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamidemono-p-toluenesulfonate

[2313] The title compound was prepared according to the proceduredescribed in Example 231 fromN-[({2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide(step 4).

[2314]¹H-NMR (CDCl₃) δ: 9.85 (1H, br.s), 7.78 (4H, d, J=8.1 Hz), 7.45(2H, d, J=7.9 Hz), 7.27-7.13 (6H, m), 7.01 (1H, s), 3.45-.343 (2H, m),3.03 (3H, s), 2.89-2.87 (2H, m), 2.79-2.73 (5H, m), 2.36 (3H, s), 2.34(3H, s), 1.74-1.65 (2H, m), 1.35-1.23 (2H, m), 0.84 (3H, t, J=7.2 Hz).

Example 2402-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-B]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate mono-hydrochloride

[2315] To a solution of2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate (Example 7, 694 mg, 1.37 mmol) inmethanol (4 ml) was added 10% HCl in methanol (2 ml) at roomtemperature. This mixture was concentrated, and treated withdiethylether to afford 624 mg (90%) of the title compound as a slightyellow solid.

[2316]¹H-NMR (DMSO-d₆) δ: 11.92 (1H, br.s), 7.76 (2H, d, J=7.9 Hz),7.49-7.39 (6H, m), 7.26 (1H, br.s), 4.98-4.88 (1H, m), 2.94-2.83 (4H,m), 2.63 (3H, s), 2.46 (3H, s), 2.34 (3H, s), 1.23 (3H, t, J=7.5 Hz),1.12 (3H, d, J=6.1 Hz).

[2317] MS (ESI) m/z: 507 [(MH)⁺], 505 [(M−H)⁻].

Example 241N-{[(2-{4-[5,7-Dimethyl-2-(3-phenylpropyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl{-4-methylbenzenesulfonamide

[2318] A mixture of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(step 4 of Example 162, 86 mg, 0.19 mmol), 4-phenylbutyric acid (37 mg,0.23 mmol) and 1- ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (40 mg, 0.21 mmol) was stirred at room temperature for 5days. The mixture was concentrated to give an orange syrup. Thismaterial was dissolved in toluene (8 ml), added p-toluenesulfonic acidmono-hydrate (3 mg, 0.02 mol), then stirred under reflux temperature for5 h. The mixture was diluted with dichloromethane and washed withdiluted hydrochloric acid. The organic layer was concentrated.Purification by TLC developing with hexane/ethyl acetate (1:3) gave 32mg (29%) of the title compound as a colorless solid.

[2319]¹H-NMR (CDCl₃) δ: 7.85 (2H, d, J=8.4 Hz), 7.31-7.01 (11H, m), 6.91(1H, s), 3.52-3.45 (2H, m), 2.83 (2H, t, J=6.4 Hz), 2.71-2.65 (2H, m),2.64 (3H, s), 2.58-2.53 (2H, m), 2.41 (3H, s), 2.39 (3H, s), 2.00-1.90(2H, m).

[2320] MS (ESI) m/z: 582 [(MH)⁺], 580 [(M−H)⁻].

Example 242N-{[(2-{4-[5,7-Dimethyl-2-(3-oxo-3-phenylpropyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[2321] The title compound was prepared according to the proceduredescribed in Example 241 fromN-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}4-methylbenzenesulfonamide(step 4 of Example 162) and 3-benzoylpropionic acid.

[2322]¹H-NMR (CDCl₃) δ: 8.04-7.14 (I11H, m), 6.90 (1H, s), 6.20-6.15(1H, m), 3.50-3.38 (4H, m), 3.03-2.81 (4H, m), 2.56 (3H, s), 2.44 (3H,s), 2.41 (3H, s).

[2323] MS (ESI) m/z: 596 [(MH)⁺], 594 [(M−H)⁻].

Example 2432-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl3-pyridinylsulfonylcarbamate

[2324] Step 1.2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylphenyl carbonate

[2325] To a stirred solution of2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethanol(step 4 of Example 104, 3.90 g, 10.6 mmol) in dichloromethane (20 mL)and pyridine (2 ml) was added dropwise phenyl chloroformate (1.6 mL,12.7 mmol), and the mixture was stirred at room temperature for 16 h.The reaction mixture was diluted with dichloromethane (50 mL), washedwith water (50 ml). The organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure. Purification by flash columnchromatography eluting with hexane/ethyl acetate (3:1) afforded 4.2 g(82%) of the title compound as a colorless syrup.

[2326]¹H NMR (CDCl₃) δ 8.12 (1H, s), 7.53-7.15 (10H, m), 4.56 (2H, t,J=6.8 Hz), 3.20 (2H, t, J=6.8 Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t,J=7.6 Hz).

[2327] MS (EI) m/z: 488 (M⁺).

[2328] Step 12.2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl3-pyridinylsulfonylcarbamate

[2329] To a stirred solution of 3-pyridinesulfonamide (Rafik, Karaman;et al., J. Am. Chem. Soc., 1992, 114, 4889, 120 mg, 0.76 mmol) in DMF (3mL) was added NaH (60% oil dispersion, 27 mg, 0.68 mmol) at roomtemperature. After 10 min., phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1, 313 mg, 0.64 mmol) was added, and the mixture was stirred for 9h at 80° C. The mixture was diluted with ethyl acetate (50 mL), andwashed with water and brine. The organic layer was dried (Na2SO4) andconcentrated. Purification by TLC developing withdichloromethane/methanol (6:1) and TLC developing withdichloromethane/methanol (10:1) gave 67 mg (19%) of the title compoundas colorless solid.

[2330]¹H-NMR (CDCl₃) δ 9.18 (1H, s), 8.73-8.72 (1H, m), 8.32-8.29 (1H,m), 8.09 (1H, s), 7.40-7.15 (6H, m), 4.33-4.29 (2H, m), 2.99-2.94 (2H,m), 2.78-2.71 (2H, m), 1.35-1.32 (3H, m).

[2331] MS (ESI) m/z: 553 (MH⁺), 551 ([M−H]⁻)

Example 2442-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl2-pyridinylsfonylcarbamate

[2332] The title compound was prepared according to the proceduredescribed in step 2 of Example 243 from 2-pyridinesulfonamnide (Naito,T.; et al., Chem. Pharm. Bull., 1955, 3, 38) and2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 243).

[2333] m.p.: 127.0-130.0° C.

[2334]¹H-NMR (CDCl₃) δ 8.76-8.73 (1H, m), 8.24-8.21 (2H, m), 8.16 (1H,s), 8.03-7.97 (1H, m), 7.62-7.56 (1H, m), 7.37 (2H, d, J=8.2 Hz), 7.23(2H, d, J=8.2 Hz), 7.17 (1H, s), 4.37 (2H, t, J=6.8 Hz), 3.01 (2H, t,J=6.8 Hz), 2.77 (2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.6 Hz).

[2335] MS (ESI) m/z: 553 (MH⁺), 551 ([M−H]⁻).

Example 2452-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl4-pyridinylsulfonylcarbamate

[2336] The title compound was prepared according to the proceduredescribed in step 2 of Example 243 from 4-pyridinesulfonamide (Comrie,A. M.; et al., J. Chem. Soc., 1958, 3514) and2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 243).

[2337]¹H-NMR (CDCl₃) δ 8.82 (2H, d, J=5.2 Hz), 8.10 (1H, s), 7.87 (2H,d, J=4.9 Hz), 7.44 (2H, d, J=7.9 Hz), 7.27 (2H, d, J=7.9 Hz), 7.20 (1H,s), 4.34 (2H, t, J=7.3 Hz), 3.04 (2H, t, J=7.3 Hz), 2.78 (2H, q, J=7.6Hz), 1.36 (3H, t, J=7.6 Hz).

[2338] MS (ESI) m/z: 553 (MH⁺), 551 ([M−H]⁻).

Example 2462-[4-(5-Acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl-1-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2339] Step 1.1-(4-{[4-(2-hydroxypropyl)phenyl]amino}-3-nitrophenyl)ethanone

[2340] The title compound was prepared according to the proceduredescribed in step 1 of Example 162 from1-(4-chloro-3-nitrophenyl)ethanone and 1-(4-aminophenyl)-2-propanol(step 1 of Example 6).

[2341]¹H-NMR (CDCl₃) δ: 9.85 (1H, br.s), 8.83-8.82 (1H, m), 7.99-7.95(1H, m), 7.33 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.18 (1H, d,J=9.0 Hz), 4.13-4.04 (1H, m), 2.87-2.72 (2H, m), 2.58 (3H, s), 1.29 (3H,d, J=6.2 Hz).

[2342] Step 2.1-(3-amino-4-{[4-(2-hydroxyprolpyl)phenyl]amino}phenyl)ethanone

[2343] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from1-(4-{[4-(2-hydroxypropyl)phenyl]amino}-3-nitrophenyl)ethanone (step 1).

[2344] MS (EI) m/z: 284 (M⁺).

[2345] Step 3.2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethylpropanoate

[2346] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-(3-amino-4-{[4-(2-hydroxypropyl)phenyl]amino}phenyl)ethanone (step 2).

[2347]¹H-NMR (CDCl₃) δ: 8.41-8.40 (1H, m), 8.83-8.82 (1H, m), 7.92-7.89(1H, m), 7.43 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 7.12-7.09 (1H,m), 5.25-5.18 (1H, m), 3.07-2.88 (2H, m), 2.80 (2H, q, J=7.3 Hz), 2.68(3H, s), 2.34-2.26 (2H, m), 1.37 (3H, q, J=7.5 Hz), 1.32 (3H, d, J=6.2Hz), 1.10 (3H, t, J=7.5 Hz).

[2348] Step 4.1-{2-ethyl-1-[4-(2-hydroxypropyl)phenyl]-1H-benzimidazol-5-yl}ethanone

[2349] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethylpropanoate (step 3).

[2350]¹H-NMR (CDCl₃) δ: 8.39 (1H, s), 7.89-7.86 (1H, m), 7.47 (2H, d,J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 7.13-7.10 (1H, m), 4.23-4.13 (1H, m),2.94-2.86 (2H, m), 2.80 (2H, q, J=7.5 Hz), 2.66 (3H, s), 1.39-1.33 (6H,m).

[2351] Step 5.2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2352] The title compound was prepared according to the proceduredescribed in Example 3 from1-{2-ethyl-1-[4-(2-hydroxypropyl)phenyl]-1H-benzimidazol-5-yl}ethanone(step 4).

[2353]¹H-NMR (CDCl₃) δ: 8.40 (1H, d, J=1.1 Hz), 7.91-7.86 (3H, m),7.32-7.24 (4H, m), 7.17 (2H, d, J=7.9 Hz), 7.07 (1H, d, J=8.4 Hz),5.09-5.03 (1H, m), 2.99-2.75 (2H, m), 2.77 (2H, q, J=7.5 Hz), 2.67 (3H,s), 2.37 (3H, s), 1.33 (3H, t, J=7.5 Hz), 1.21 (3H, d, J=6.1 Hz).

[2354] MS (ESI) m/z: 520 (MH⁺), 518 ([M−H]⁻).

Example 2472-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl-(4-methylphenyl)sulfonylcarbamate

[2355] Step 1.1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol

[2356] The title compound was prepared according to the proceduredescribed in step 1 of Example 162 from2,4-dichloro-5-nitrobenzotrifluoride and 1-(4-aminophenyl)-2-propanol(step 1 of Example 6).

[2357]¹H-NMR (CDCl₃) δ: 9.69 (1H, br.s), 8.58 (1H, s), 7.36 (2H, d,J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.20 (1H, s), 4.13-4.06 (1H, m),2.88-2.73 (2H, m), 1.48 (1H, d, J=4.2 Hz), 1.30 (3H, d, J=6.2 Hz).

[2358] Step 2.1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol

[2359] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol(step 1).

[2360]¹H-NMR (CDCl₃) δ: 7.17 (1H, s), 7.15 (2H, d, J=8.4 Hz), 7.06 (1H,s), 6.90 (2H, d, J=8.4 Hz), 4.05-3.98 (1H, m), 2.79-2.61 (2H, m), 1.26(3H, d, J=6.3 Hz).

[2361] Step 3.2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylpropanoate

[2362] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol(step 2).

[2363] MS (EI) m/z: 438 (M⁺).

[2364] Step 4.1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol

[2365] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylpropanoate (step 3).

[2366]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.47 (2H, d, J=8.4 Hz), 7.28 (2H,d, J=8.4 Hz), 7.21 (1H, s), 4.20-4.10 (1H, m), 2.95-2.83 (2H, m), 2.79(2H, q, J=7.5 Hz), 1.56 (1H, d, J=4.2 Hz), 1.36 (3H, t, J=7.5 Hz), 1.34(3H, d, J=6.2 Hz).

[2367] Step 5.2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2368] The title compound was prepared according to the proceduredescribed in Example 3 from1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol(step 4).

[2369]¹H-NMR (CDCl₃) δ: 8.09 (1H, s), 7.87 (2H, d, J=8.4 Hz), 7.41 (2H,d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.21 (1H,s), 5.06-5.00 (1H, m), 3.04-2.74 (4H, m), 2.40 (3H, s), 1.36 (3H, t,J=7.5 Hz), 1.23 (3H, d, J=6.2 Hz).

[2370] MS (ESI) m/z: 580 (MH⁺), 578 ([M−H]⁻).

Example 248(1S)-2-[4-(5-Acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2371] Step 1. (2S)-1-(4-nitrophenyl)-2-propanol and(1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate

[2372] To a mixture of 1-(4-nitrophenyl)-2-propanol (Schadt, F. L. etal., J. Am. Chem. Soc., 1978, 100, 228., 2.5 g, 13.8 mmol) and propanoicanhydride (1.8 g, 13.8 mmol) in benzene (34 ml) was added LipasePS/Celite (0.5 g, Bianichi, D. et al. J. Org. Chem. 1988, 53, 5531). Theresulting mixture was stirred at room temperature for 72 h. The reactionmixture was filtered through a pad of Celite. The filtrate was washedwith saturated aqueous sodium hydrogencarbonate and brine. The organiclayer was dried (MgSO4), and concentrated. Purification by flash columnchromatography eluting with hexane/diethyl ether (4:1 to 1:1) afforded1.91 g (58%) of (1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate as aslight yellow oil and 1.14 g (46%) of (2S)-1-(4-nitrophenyl)-2-propanolas a colorless solid (93% e.e.). Recrystallization of 1.14 g of(2S)-1-(4-nitrophenyl)-2-propanol from hexane/diethyl ether afforded 617mg of a colorless needle (99% e.e.).

[2373] (1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate

[2374]¹H-NMR (CDCl₃) δ: 8.16 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=8.8 Hz),5.22-5.11 (1H, m), 3.04-2.87 (2H, m), 2.30-2.19 (2H, m), 1.26 (3H, d,J=6.1 Hz), 1.07 (3H, t, J=7.5 Hz).

[2375] (2S)-1-(4-nitrophenyl)-2-propanol

[2376]¹H-NMR (CDCl₃) δ: 8.18 (2H, d, J=8.8 Hz), 7.39 (2H, d, J=8.8 Hz),4.14-4.04 (1H, m), 2.92-2.79 (2H, m), 1.49 (1H, d, J=4.0 Hz), 1.28 (3H,d, J=6.1 Hz).

[2377] [α]²³ _(D)+31.0° (c 1.00, diethyl ether).

[2378] Step 2. (2S)-1-(4-aminophenyl)-2-propanol

[2379] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from (2S)-1-(4-nitrophenyl)-2-propanol(step 1).

[2380]¹H-NMR (CDCl₃) δ: 7.00 (2H, d, J=8.4 Hz), 6.65 (2H, d, J=8.4 Hz),3.99-3.89 (1H, m), 3.60 (2H, br.s) 2.73-2.52 (2H, m), 1.22 (3H, d, J=6.2Hz).

[2381] Step 3.1-[4-({4-[(2S)-2-hydroxypropyl]phenyl Iamino)-3-nitrophenyl]ethanone

[2382] The title compound was prepared according to the proceduredescribrd in step 1 of Example 162 from1-(4-chloro-3-nitrophenyl)ethanone and (2S)-1-(4-aminophenyl)-2-propanol(step 2).

[2383]¹H-NMR (CDCl₃) δ: 9.85 (1H, br.s), 8.83-8.82 (1H, m), 7.99-7.95(1H, m), 7.33 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.18 (1H, d,J=9.0 Hz), 4.13-4.04 (1H, m), 2.87-2.72 (2H, m), 2.58 (3H, s), 1.29 (3H,d, J=6.2 Hz).

[2384] Step 4.1-[3-amino-4-({4-[(2S)-2-hydroxypropyl]phenyl}amino)phenyl]ethanone

[2385] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from1-[({4-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-3-nitrophenyl]ethanone(step 3).

[2386] MS (EI) m/z: 284 (M⁺).

[2387] Step 5.(1S)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethylpropanoate

[2388] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-[3-amino-4-({4-[(2S)-2-hydroxypropyl]phenyl}amino)phenyl]ethanone(step 4).

[2389]¹H-NMR (CDCl₃) δ: 8.41-8.40 (1H, m), 8.83-8.82 (1H, m), 7.92-7.89(1H, m), 7.43 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 7.12-7.09 (1H,m), 5.25-5.18 (1H, m), 3.07-2.88 (2H, m), 2.80 (2H, q, J=7.3 Hz), 2.68(3H, s), 2.34-2.26 (2H, m), 1.37 (3H, q, J=7.5 Hz), 1.32 (3H, d, J=6.2Hz), 1.10 (3H, t, J=7.5 Hz).

[2390] Step 6.1-(2-ethyl-1-{4-[(2S)-2-hydroxypropyl]phenyl}-1H-benzimidazol-5-yl)ethanone

[2391] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from(1S)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethylpropanoate (step 5).

[2392]¹H-NMR (CDCl₃) δ: 8.39 (1H, d, J=1.1 Hz), 7.87 (1H, dd, J=8.6, 1.1Hz), 7.48 (2H, d, J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.12 (1H, d, J=8.6Hz), 4.22-4.12 (1H, m), 2.94-2.89 (2H, m), 2.80 (2H, q, J=7.5 Hz), 2.69(3H, s), 2.42 (1H, br.s), 1.37 (3H, t, J=7.5 Hz), 1.33 (3H, d, J=6.2Hz).

[2393] Step 7.(1S)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2394] The title compound was prepared according to the proceduredescribed in Example 3 from1-(2-ethyl-1-{4-[(2S)-2-hydroxypropyl]phenyl}-1H-benzimidazol-5-yl)ethanone(step 6).

[2395]¹H-NMR (CDCl₃) δ: 8.40 (1H, d, J=1.1 Hz), 7.91-7.86 (3H, m),7.32-7.24 (4H, m), 7.17 (2H, d, J=7.9 Hz), 7.07 (1H, d, J=8.4 Hz),5.09-5.03 (1H, m), 2.99-2.75 (2H, m), 2.77 (2H, q, J=7.5 Hz), 2.67 (3H,s), 2.37 (3H, s), 1.33 (3H, t, J=7.5 Hz), 1.21 (3H, d, J=6.1 Hz).

[2396] MS (ESI) m/z: 520 (MH⁺), 518 ([M−H]⁻). [α]²⁴ _(D) −3.09° (c0.120, methanol)

Example 249(1R)-2-[4-(5-Acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2397] Step 1. (2R)-1-(4-nitrophenyl)-2-propanol

[2398] To a solution of (1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate(step 1 of Example 248, 1.91 g, 8.05 mmol) in ethanol (20 ml) was added2N aqueous NaOH (5 ml) at room temperature. The resulting mixture wasstirred at room temperature for 2 h. The reaction mixture was pouredinto water, extracted with diethyl ether (2×50 ml). The organic layerwas washed with brine, dried (MgSO4), and concentrated. Purification byflash column chromatography eluting with hexane/diethyl ether (1:1)afforded 1.16 g (80%) of title compound as a colorless solid (79% e.e.).Recrystallization from hexane/diethyl ether afforded 717 mg of acolorless needle (99% e.e.).

[2399]¹H-NMR (CDCl₃) δ: 8.18 (2H, d, J=8.8 Hz), 7.39 (2H, d, J=8.8 Hz),4.14-4.04 (1H, m), 2.92-2.79 (2H, m), 1.49 (1H, d, J=4.0 Hz), 1.28 (3H,d, J=6.1 Hz).

[2400] [α]²³ _(D) −32.6° (c 1.00, diethyl ether).

[2401] Step 2. (2R)-1-(4-aminophenyl)-2-propanol

[2402] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from (2R)-1-(4-nitrophenyl)-2-propanol(step 1).

[2403]¹H-NMR (CDCl₃) δ: 7.00 (2H, d, J=8.4 Hz), 6.65 (2H, d, J=8.4 Hz),3.99-3.89 (1H, m), 3.60 (2H, br.s) 2.73-2.52 (2H, m), 1.22 (3H, d, J=6.2Hz).

[2404] Step 3.1-[4-({4-[(2R)-2-hydroxypropyl]phenyl}amino)-3-nitrophenyl]ethanone

[2405] The title compound was prepared according to the proceduredescribed in step 1 of Example 162 from1-(4-chloro-3-nitrophenyl)ethanone and (2R)-1-(4-aminophenyl)-2-propanol(step 2).

[2406]¹H-NMR (CDCl₃) δ: 9.85 (1H, br.s), 8.83-8.82 (1H, m), 7.99-7.95(1H, m), 7.33 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.18 (1H, d,J=9.0 Hz), 4.134.04 (1H, m), 2.87-2.72 (2H, m), 2.58 (3H, s), 1.29 (3H,d, J=6.2 Hz).

[2407] Step 4.1-[3-amino-4-({4-[(2R)-2-hydroxypropyl]phenyl}amino)phenyl]ethanone

[2408] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from1-[4-({4-[(2R)-2-hydroxypropyl]phenyl}amino)-3-nitrophenyl]ethanone(step 3).

[2409] MS (EI) m/z: 284 (M⁺).

[2410] Step 5.(1R)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethylpropanoate

[2411] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-[3-amino-4-({4-[(2R)-2-hydroxypropyl]phenyl}amino)phenyl]ethanone(step 4).

[2412]¹H-NMR (CDCl₃) δ: 8.41-8.40 (1H, m), 8.83-8.82 (1H, m), 7.92-7.89(1H, m), 7.43 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 7.12-7.09 (1H,m), 5.25-5.18 (1H, m), 3.07-2.88 (2H, m), 2.80 (2H, q, J=7.3 Hz), 2.68(3H, s), 2.34-2.26 (2H, m), 1.37 (3H, q, J=7.5 Hz), 1.32 (3H, d, J=6.2Hz), 1.10 (3H, t, J=7.5 Hz).

[2413] Step 6.1-(2-ethyl-1-{4-[(2R)-2-hydroxypropyl]phenyl}-1H-benzimidazol-5-yl)ethanone

[2414] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from(1R)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethylpropanoate (step 5).

[2415]¹H-NMR (CDCl₃) δ: 8.39 (1H, d, J=1 Hz), 7.87 (1H, dd, J=8.6, 1.1Hz), 7.48 (2H, d, J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.12 (1H, d, J=8.6Hz), 4.22-4.12 (1H, m), 2.94-2.89 (2H, m), 2.80 (2H, q, J=7.5 Hz), 2.69(3H, s), 2.42 (1H, br.s), 1.37 (3H, t, J=7.5 Hz), 1.33 (3H, d, J=6.2Hz).

[2416] Step 7.(1R)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2417] The title compound was prepared according to the proceduredescribed in Example 3 from1-(2-ethyl-1-{4-[(2R)-2-hydroxypropyl]phenyl}-1H-benzimidazol-5-yl)ethanone(step 6).

[2418]¹H-NMR (CDCl₃) δ: 8.40 (1H, d, J=1.1 Hz), 7.91-7.86 (3H, m),7.32-7.24 (4H, m), 7.17 (2H, d, J=7.9 Hz), 7.07 (1H, d, J=8.4 Hz),5.09-5.03 (1H, m), 2.99-2.75 (2H, m), 2.77 (2H, q, J=7.5 Hz), 2.67 (3H,s), 2.37 (3H, s), 1.33 (3H, t, J=7.5 Hz), 1.21 (3H, d, J=6.1 Hz).

[2419] MS (ESI) m/z: 520 (MH⁺), 518 ([M−H]⁻). [α]²⁴ _(D)+6.05° (c 0.118,methanol).

Example 250(1S)-2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2420] Step 1.(2S)-1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol

[2421] The title compound was prepared according to the proceduredescribed in step 1 of Example 162 from2,4-dichloro-5-nitrobenzotrifluoride and(2S)-1-(4-aminophenyl)-2-propanol (step 2 of Example 248).

[2422]¹H-NMR (CDCl₃) δ: 9.69 (1H, br.s), 8.58 (1H, s), 7.36 (2H, d,J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.20 (1H, s), 4.13-4.06 (1H, m),2.88-2.73 (2H, m), 1.48 (1H, d, J=4.2 Hz), 1.30 (3H, d, J=6.2 Hz).

[2423] Step 2.(2S)-1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol

[2424] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from(2S)-1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol(step 1).

[2425]¹H-NMR (CDCl₃) δ: 7.17 (1H, s), 7.15 (2H, d, J=8.4 Hz), 7.06 (1H,s), 6.90 (2H, d, J=8.4 Hz), 4.05-3.98 (1H, m), 2.79-2.61 (2H, m), 1.26(3H, d, J=6.3 Hz).

[2426] Step 3.(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylpropanoate

[2427] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from(2S)-1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol(step 2).

[2428] MS (EI) m/z: 438 (M⁺).

[2429] Step 4.(2S)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol

[2430] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylpropanoate (step 3).

[2431]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.47 (2H, d, J=8.4 Hz), 7.28 (2H,d, J=8.4 Hz), 7.21 (1H, s), 4.20-4.10 (1H, m), 2.95-2.83 (2H, m), 2.79(2H, q, J=7.5 Hz), 1.56 (1H, d, J=4.2 Hz), 1.36 (3H, t, J=7.5 Hz), 1.34(3H, d, J=6.2 Hz).

[2432] Step 5.(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-11H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2433] The title compound was prepared according to the proceduredescribed in Example 3 from(2S)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol(step 4).

[2434] m.p.: 200.3° C.

[2435]¹H-NMR (CDCl₃) δ: 8.09 (1H, s), 7.87 (2H, d, J=8.4 Hz), 7.41 (2H,d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.21 (1H,s), 5.06-5.00 (1H, m), 3.04-2.74 (4H, m), 2.40 (3H, s), 1.36 (3H, t,J=7.5 Hz), 1.23 (3H, d, J=6.2 Hz).

[2436] MS (ESI) m/z: 580 (MH⁺), 578 ([M−H]⁻).

[2437] [α]²⁴ _(D)+1.31° (c 0.398, methanol)

[2438] ee: 98%.

Example 251(1S)-2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate mono-p-toluenesulfonate

[2439] The title compound was prepared according to the proceduredescribed in Example 231 from(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate (step 5 of Example 250).

[2440]¹H-NMR (DMSO-d₆) δ: 11.91 (1H, br.s), 8.23 (1H, s), 7.75 (2H, d,J=8.3 Hz), 7.50-7.37 (9H, m), 7.11 (2H, d, J=8.1 Hz), 4.97-4.91 (1H, m),2.92-2.76 (4H, m), 2.30 (3H, s), 2.27 (3H, s), 1.24 (3H, t, J=7.3 Hz),1.14 (3H, d, J=6.2 Hz).

[2441] MS (ESI) m/z: 580 (MH⁺), 578 ([M−H]⁻).

Example 252(1R)-2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2442] Step 1.(2R)-1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol

[2443] The title compound was prepared according to the proceduredescribed in step 1 of Example 162 from2,4-dichloro-5-nitrobenzotrifluoride and(2R)-1-(4-aminophenyl)-2-propanol (step 2 of Example 249).

[2444]¹H-NMR (CDCl₃) δ: 9.69 (1H, br.s), 8.58 (1H, s), 7.36 (2H, d,J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.20 (1H, s), 4.13-4.06 (1H, m),2.88-2.73 (2H, m), 1.48 (1H, d, J=4.2 Hz), 1.30 (3H, d, J=6.2 Hz).

[2445] Step 2.(2R)-1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]aminolphenyl)-2-propanol

[2446] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from(2R)-1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol(step 1).

[2447]¹H-NMR (CDCl₃) δ: 7.17 (1H, s), 7.15 (2H, d, J=8.4 Hz), 7.06 (1H,s), 6.90 (2H, d, J=8.4 Hz), 4.05-3.98 (1H, m), 2.79-2.61 (2H, m), 1.26(3H, d, J=6.3 Hz).

[2448] Step 3.(1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylpropanoate

[2449] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from(2R)-1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol(step 2).

[2450] MS (EI) m/z: 438 (M⁺).

[2451] Step 4.(2R)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol

[2452] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from(1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylpropanoate (step 3).

[2453]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.47 (2H, d, J=8.4 Hz), 7.28 (2H,d, J=8.4 Hz), 7.21 (1H, s), 4.20-4.10 (1H, m), 2.95-2.83 (2H, m), 2.79(2H, q, J=7.5 Hz), 1.56 (1H, d, J=4.2 Hz), 1.36 (3H, t, J=7.5 Hz), 1.34(3H, d, J=6.2 Hz).

[2454] Step 5.(1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2455] The title compound was prepared according to the proceduredescribed in Example 3 from(2R)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol(step 4).

[2456] m.p.: 199.9° C.

[2457]¹H-NMR (CDCl₃) δ: 10.70 (1H, br.s), 8.10 (1H, s), 7.89 (2H, d,J=8.3 Hz), 7.40 (2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz), 7.22 (2H, d,J=8.3 Hz), 7.20 (1H, s), 5.32-5.00 (1H, m), 3.04-2.82 (2H, m), 2.78 (2H,q, J=7.5 Hz), 2.40 (3H, s), 1.36 (3H, t, J=7.5 Hz), 1.23 (3H, d, J=6.2Hz).

[2458] MS (ESI) m/z: 580 (MH⁺), 578 ([M−H]⁻).

[2459] [α]²⁴ _(D) −2.19° (c 0.402, methanol).

[2460] ee: 97%.

Example 253N-{[(2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[2461] Step 1.1-[4-(2-azidopropyl)phenyl]-6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole

[2462] To a stirred solution of1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol(step 8 of Example 247, 1.96 g, 5.12 mmol), triphenylphosphine (1.75 g,6.66 mmol) and diphenylphosphoryl azide (1.83 mg, 6.66 mmol) intetrahydrofuran (15 ml) was added diethyl azodicarboxylate (1.16 mg,6.66 mmol) at room temperature. The resulting mixture was stirred attemperature for 3 h, then under reflux temperature. The mixture wasdiluted with ethyl acetate and washed with water and brine. The organiclayer was dried (Na2SO4), and concentrated. Purification by flash columnchromatography eluting with hexane/ethyl acetate (2:1) and TLCdeveloping with hexane/ethyl acetate (1:1) afforded 769 mg (37%) of thetitle compound as a slight yellow syrup.

[2463]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.47 (2H, d, J=8.3 Hz), 7.30 (2H,d, J=8.3 Hz), 7.21 (1H, s), 3.85-3.77 (1H, m), 2.92-2.89 (2H, m), 2.80(2H, q, J=7.5 Hz), 1.37 (3H, d, J=6.6 Hz), 1.36 (3H, t, J=7.5 Hz).

[2464] MS (ESI) m/z: 408 (MH⁺).

[2465] Step 2.2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl]-1-methylethylamine

[2466] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidopropyl)phenyl]-6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole(step 1).

[2467]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.44 (2H, d, J=8.3 Hz), 7.28 (2H,d, J=8.3 Hz), 7.21 (1H, s), 3.49-3.26 (1H, m), 2.86-2.95 (2H, m), 2.79(2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz), 1.20 (3H, d, J=6.2 Hz).

[2468] Step 3.N-{[(2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[2469] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylamine(step 2).

[2470]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.73 (2H, d, J=8.4 Hz), 7.41 (2H,d, J=8.3 Hz), 7.29-7.23 (4H, m), 7.17 (1H, s), 4.20-4.11 (1H, m),2.99-2.82 (2H, m), 2.78 (2H, q, J=7.3 Hz), 2.38 (3H, s), 1.35 (3H, t,J=7.3 Hz), 1.24 (3H, d, J=6.6 Hz).

[2471] MS (ESI) m/z: 579 (MH⁺), 577 ([M−H]⁻).

Example 254N-{[((1S)-2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[2472] Step 1.1-[4-[(2s)-2-azidopropyl)phenyl]-6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole

[2473] The title compound was prepared according to the proceduredescribed in step 1 of Example 253 from(2R)-1-(4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol(step 4 of Example 252).

[2474]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.46 (2H, d, J=7.9 Hz), 7.29 (2H,d, J=7.9 Hz), 7.21 (1H, s), 3.84-3.77 (1H, m), 2.92-2.89 (2H, m), 2.79(2H, q, J=7.6 Hz), 1.39-1.33 (6H, m).

[2475] Step 2.(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylamine

[2476] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-[(2s)-2-azidopropyl)phenyl]-6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole(step 1).

[2477]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.44 (2H, d, J=8.3 Hz), 7.28 (2H,d, J=8.3 Hz), 7.21 (1H, s), 3.49-3.26 (1H, m), 2.86-2.65 (2H, m), 2.79(2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz), 1.20 (3H, d, J=6.2 Hz).

[2478] Step 3.N-{[((1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[2479] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylamine(step 2).

[2480] m.p.: 141.0-143.0° C.

[2481]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.73 (2H, d, J=8.3 Hz), 7.41 (2H,d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz), 7.25 (2H, d, J=8.3 Hz), 7.17 (1H,s), 6.58 (1H, d, J=7.7 Hz), 4.22-4.14 (1H, m), 2.82-2.30 (2H, m), 2.78(2H, q, J=7.6 Hz), 2.39 (3H, s), 1.35 (3H, t, J=7.5 Hz), 1.24 (3H, d,J=6.6 Hz).

[2482] MS (ESI) m/z: 579 (MH⁺), 691 ([M+CF₃COOH—H]⁻).

[2483] [α]²⁴ _(D) −5.08° (c 0.394, methanol)

[2484] ee: 99%.

Example 255N-{[((1R)-2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[2485] Step 1.1-[4-[(2R)-2-azidopropyl)phenyl]-6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole

[2486] The title compound was prepared according to the proceduredescribed in step 1 of Example 253 from(2S)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol(step 4 of Example 250).

[2487]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.46 (2H, d, J=7.9 Hz), 7.29 (2H,d, J=7.9 Hz), 7.21 (1H, s), 3.84-3.77 (1H, m), 2.92-2.89 (2H, m), 2.79(2H, q, J=7.6 Hz), 1.39-1.33 (6H, m).

[2488] Step 2.(1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl1-1-methylethylamine

[2489] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-[(2R)-2-azidopropyl)phenyl]-6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole(step 1).

[2490]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.44 (2H, d, J=8.3 Hz), 7.28 (2H,d, J=8.3 Hz), 7.21 (1H, s), 3.49-3.26 (1H, m), 2.86-2.65 (2H, m), 2.79(2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz), 1.20 (3H, d, J=6.2 Hz).

[2491] Step 3.N-{[((1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[2492] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from(1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylamine(step 2).

[2493] m.p.: 138.0-141.0° C.

[2494]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.73 (2H, d, J=8.3 Hz), 7.41 (2H,d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz), 7.25 (2H, d, J=8.3 Hz), 7.17 (1H,s), 6.58 (1H, d, J=7.7 Hz), 4.22-4.14 (1H, m), 2.82-2.30 (2H, m), 2.78(2H, q, J=7.6 Hz), 2.39 (3H, s), 1.35 (3H, t, J=7.5 Hz), 1.24 (3H, d,J=6.6 Hz).

[2495] MS (ESI) m/z: 579 (MH⁺), 691 ([M+CF₃COOH—H]⁻). [α]²⁴ _(D)+3.430(c 0.408, methanol).

[2496] ee: 99%.

Example 2562-{4-[6-Chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenylIethyl (4-methylphenyl)sulfonylcarbamate

[2497] Step 1.2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[2498] A mixture of2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol(step 2 of Example 104, 2.28 g, 5.85 mmol) and1H-pyrazole-3-carbaldehyde (562 mg, 2.85 mmol) in ethanol (35 ml) wasstirred under reflux temperature for 1 h. The mixture was concentratedand dissolved in benzene (40 ml). To this solution was added leadtetraacetate (2.85 g, 6.44 mmol) at rt. After stirring at roomtemperature for 18 h, to the mixture were added saturated aqueous sodiumhydrogencarbonate (50 ml) and ethyl acetate. The organic layer wasseparated and washed with brine, dried (Na2SO4) and concentrated.Purification by flash column chromatography eluting withdichloromethane/methanol (20:1 to 10:1), then dichloromethane/2-propanol(5:1) afforded 979 mg (41%) of the title compound as a slight brownsolid.

[2499]¹H-NMR (CDCl₃/CD3OD=4/1) δ: 8.12 (1H, br.s), 7.74 (1H, s), 7.59(1H, br.s), 7.47 (2H, d, J=7.9 Hz), 7.34-7.30 (3H, m), 6.36 (1H, br.s),3.87 (2H, br.t, J=6.8 Hz), 2.95 (2H, t, J=6.8 Hz).

[2500] MS (ESI) m/z: 407 (MH⁺), 405 ([M−H]⁻).

[2501] Step 2.2-4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methyl]henyl)sulfonylcarbamate

[2502] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl)ethanol(step 1).

[2503]¹H-NMR (CDCl₃) δ: 8.18 (1H, s), 7.91 (2H, d, J=8.3 Hz), 7.54-7.53(1H, m), 7.34-7.23 (8H, m), 6.31 (1H, br.s), 4.40 (2H, t, J=6.4 Hz),3.01 (2H, t, J=6.4 Hz), 2.42 (3H, s).

[2504] MS (ESI) m/z: 604 (MH⁺), 602 ([M−H]⁻).

Example 2572-{4-[6-Chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate mono-p-toluenesulfonate

[2505] The title compound was prepared according to the proceduredescribed in Example 231 from2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl]ethyl(4-methylphenyl)sulfonylcarbamate (step 2 of Example 256).

[2506]¹H-NMR (DMSO-d₆) δ: 8.24 (1H, s), 7.77-7.74 (2H, m), 7.48-7.38(10H, m), 7.26 (1H, s), 7.11 (2H, d, J=7.9 Hz), 6.44 (1H, br.s),4.30-4.20 (2H, m), 2.98-2.93 (2H, m), 2.33 (3H, s), 2.27 (3H, s).

[2507] MS (ESI) m/z: 604 (MH⁺), 602 ([M−H]⁻).

Example 258(1S)-2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate mono-hydrochloride

[2508] Step 1.(2S)-1-{4-[(-4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-propanol

[2509] The title compound was prepared according to the proceduredescribed in step 1 of Example 162 from2-chloro-4,6-dimethyl-3-nitropyridine (step 2 of Example 1) and(2S)-1-(4-aminophenyl)-2-propanol (step 2 of Example 248).

[2510]¹H-NMR (CDCl₃) δ: 9.58 (1H, br.s), 7.59 (2H, d, J=8.6 Hz), 7.19(2H, d, J=8.6 Hz), 6.53 (1H, s), 4.05-3.98 (1H, m), 2.82-2.63 (2H, m),2.55 (3H, s), 2.43 (3H, s), 1.26 (3H, d, J=6.3 Hz).

[2511] Step 2.(2S)-1-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}-2-propanol

[2512] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from(2S)-1-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-propanol(step 1).

[2513]¹H-NMR (CDCl₃) δ: 7.13-7.07 (4H, m), 6.60 (1H, s), 6.21 (1H,br.s), 4.02-3.91 (1H, m), 3.26 (2H, br.s), 2.77-2.57 (2H, m), 2.37 (3H,s), 2.20 (3H, s), 1.24 (3H, d, J=6.1 Hz).

[2514] Step 3.(1S)-2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethylpropanoate

[2515] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from(2S)-1-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl)-2-propanol(step 2).

[2516] MS (EI) m/z: 365 (M⁺).

[2517] Step 4.(2S)-1-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-2-propanol

[2518] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from(1S)-2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethylpropanoate (step 3).

[2519]¹H-NMR (CDCl₃) δ: 7.42 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz),6.91 (1H, s), 4.18-4.05 (1H, m), 2.92-2.75 (4H, m), 2.66 (3H, s), 2.52(3H, s), 1.34-1.25 (6H, m)

[2520] Step 5.(1S)-2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2521] The title compound was prepared according to the proceduredescribed i n Example 3 from(2S)-1-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-2-propanol(step 4).

[2522]¹H-NMR (CDCl₃) δ: 7.92 (2H, d, J=8.2 Hz), 7.33 (2H, d, J=8.2 Hz),7.30-7.26 (4H, m), 5.14-5.02 (1H, m), 2.99-2.77 (4H, m), 2.66 (3H, s),2.51 (3H, s), 2.42 (3H, s), 1.29-1.23 (6H, m).

[2523] MS (ESI) m/z: 507 (MH⁺), 505 ([M−H]⁻).

[2524] Step 6.2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylTphenyl)sulfonylcarbamate mono-hydrochloride

[2525] The title compound was prepared according to the proceduredescribed in Example 240 from(1S)-2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate (step 5).

[2526]¹H-NMR (DMSO-d₆) δ: 11.92 (1H, br.s), 7.76 (2H, d, J=7.9 Hz),7.49-7.39 (6H, m), 7.26 (1H, br.s), 4.98-4.88 (1H, m), 2.94-2.83 (4H,m), 2.63 (3H, s), 2.46 (3H, s), 2.34 (3H, s), 1.23 (3H, t, J=7.5 Hz),1.12 (3H, d, J=6.1 Hz).

[2527] MS (ESI) m/z: 507 [(MH)⁺], 505 [(M−H)⁻]. [α]²⁴ _(D) −12.49° (c1.014, methanol).

Example 2592-[4-(6-Acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2528] Step 1.1-[6-({4-[2-hydroxypropyl]phenyl}amino)-5-nitro-3-pyridinyl]ethanone

[2529] The title compound was prepared according to the proceduredescribed in step 1 of Example 162 from1-(6-chloro-5-nitro-3-pyridinyl)ethanone (Paul, B. et al. J. Med. Chem.,1990, 33, 2231-2239.) and 1-(4-aminophenyl)-2-propanol (step 1 ofExample 6).

[2530]¹H-NMR (CDCl₃) δ: 10.37 (1H, br.s), 9.06-9.03 (2H, m), 7.60 (2H,d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 4.104.00 (1H, m), 2.86-2.69 (2H,m), 2.60 (3H, s), 1.53 (1H, d, J=4.0 Hz), 1.28 (3H, d, J=6.2 Hz).

[2531] MS (EI) m/z: 315 (M⁺).

[2532] Step 2.1-[5-amino-6-({4-[(2-hydroxypropyl]phenyl}amino)-3-pyridinyl]ethanone

[2533] To a solution of1-[6-({4-[2-hydroxypropyl]phenyl}amino)-5-nitro-3-pyridinyl]ethanone(step 1, 1.54 g, 4.88 mmol) in tetrahydrofuran (10 ml) and ethanol (30ml) was added 10% palladium on carbon (150 mg). The resulting mixturewas stirred for 19 h under hydrogen atmosphere. The mixture was filteredthrough a pad of Celite and the filtrate was concentrated to afford 1.74g (100%) of the title compound as green syrup.

[2534]¹H-NMR (CDCl₃) δ: 8.46 (1H, d, J=1.8 Hz), 7.56 (1H, d, J=1.8 Hz),7.50 (2H, d, J=8.3 Hz), 7.20 (2H, d, J=8.3 Hz), 6.85 (1H, br.s),3.76-3.67 (1H, m), 3.38 (2H, br.s), 2.81-2.62 (2H, m), 2.53 (3H, s),1.26 (3H, d, J=6.1 Hz).

[2535] Step 3.2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethylpropanoate

[2536] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-[5-amino-6-({4-[(2-hydroxypropyl]phenyl}amino)-3-pyridinyl]ethanone(step 2).

[2537] MS (EI) m/z: 379 (M⁺).

[2538] Step 4.1-(2-ethyl-3-{4-[2-hydroxypropyl]phenyl}-3H-imidazo[4,5-b]pyridin-6-yl)ethanone

[2539] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethylpropanoate (step 3).

[2540]¹H-NMR (CDCl₃) δ: 8.93 (1H, d, J=1.8 Hz), 8.59 (1H, d, J=1.8 Hz),7.48 (2H, d, J=8.3 Hz), 7.36 (2H, d, J=8.3 Hz), 4.18-4.08 (1H, m),2.94-2.80 (2H, m), 2.63 (3H, s), 1.39 (3H, t, J=7.5 Hz), 1.33 (3H, d,J=6.2 Hz).

[2541] Step 5.2-[4-(6acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2542] The title compound was prepared according to the proceduredescribed in Example 3 from1-(2-ethyl-3-{4-[2-hydroxypropyl]phenyl}-3H-imidazo[4,5-b]pyridin-6-yl)ethanone(step 4).

[2543]¹H-NMR (CDCl₃) δ: 8.93 (1H, d, J=1.8 Hz), 8.60 (1H, d, J=1.8 Hz),7.92 (2H, d, J=8.4 Hz), 7.38-7.29 (6H, m), 5.12-5.03 (1H, m), 3.03-2.82(4H, m), 2.69 (3H, s), 2.43 (3H, s), 1.28-1.24 (6H, m).

[2544] MS (ESI) m/z: 521 [(MH)⁺], 519 [(M−H)⁻].

Example 260(1S)-2-[4-(6-Acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3yl)phenyl]-1-methylethyl(4-methylphenyl)sulfoylcarbamate

[2545] Step 1.1-[6-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-5-nitro-3-pyridinyl]ethanone

[2546] The title compound was prepared according to the proceduredescribed in step 1 of Example 162 from1-(6-chloro-5-nitro-3-pyridinyl)ethanone (Paul, B. et al. J. Med. Chem.,1990, 33, 2231-2239.) and (2S)-1-(4-aminophenyl)-2-propanol (step 2 ofExample 248).

[2547]¹H-NMR (CDCl₃) δ: 10.37 (1H, br.s), 9.06-9.03 (2H, m), 7.60 (2H,d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 4.104.00 (1H, m), 2.86-2.69 (2H,m), 2.60 (3H, s), 1.53 (1H, d, J=4.0 Hz), 1.28 (3H, d, J=6.2 Hz).

[2548] Step 2.1-[5-amino-6-(4-[(2S)-2-hydroxyproipyl]phenyl}amino)-3-pyridinyl]ethanone

[2549] The title compound was prepared according to the proceduredescribed in step 2 of Example 259 from1-[6-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-5-nitro-3-pyridinyl]ethanone(step 1).

[2550]¹H-NMR (CDCl₃) δ: 8.46 (1H, d, J=1.8 Hz), 7.56 (1H, d, J=1.8 Hz),7.50 (2H, d, J=8.3 Hz), 7.20 (2H, d, J=8.3 Hz), 6.85 (1H, br.s),3.76-3.67 (1H, m), 3.38 (2H, br.s), 2.81-2.62 (2H, m), 2.53 (3H, s),1.26 (3H, d, J=6.1 Hz).

[2551] Step 3.(1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethylpropanoate

[2552] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-[5-amino-6-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-3-pyridinyl]ethanone(step 2).

[2553] MS (EI) m/z: 379 (M⁺).

[2554] Step 4.1-(2-ethyl-3-≡4-[(2S)-2-hydroxypropyl]phenyl}-3H-imidazo[4,5-b]pyridin-6-yl)ethanone

[2555] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from(1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethylpropanoate (step 3).

[2556]¹H-NMR (CDCl₃) δ: 8.93 (1H, d, J=1.8 Hz), 8.59 (1H, d, J=1.8 Hz),7.48 (2H, d, J=8.3 Hz), 7.36 (2H, d, J=8.3 Hz), 4.18-4.08 (1H, m),2.94-2.80 (2H, m), 2.68 (3H, s), 1.39 (3H, t, J=7.5 Hz), 1.33 (3H, d,J=6.2 Hz).

[2557] Step 5.(1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate

[2558] The title compound was prepared according to the proceduredescribed in Example 3 from1-(2-ethyl-3-{4-[(2S)-2-hydroxypropyl]phenyl}-3H-imidazol[4,5-b]-pyridin-6-yl)ethanone(step 4).

[2559]¹H-NMR (CDCl₃) δ: 8.93 (1H, d, J=1.8 Hz), 8.60 (1H, d, J=1.8 Hz),7.92 (2H, d, J=8.4 Hz), 7.38-7.29 (6H, m), 5.12-5.03 (1H, m), 3.03-2.82(4H, m), 2.69 (3H, s), 2.43 (3H, s), 1.28-1.24 (6H, m).

[2560] MS (ESI) m/z: 521 [(MH)⁺], 519 [(M−H)⁻].

Example 261(1S)-2-4-(6-Acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate mono-p-toluenesulfonate

[2561] The title compound was prepared according to the proceduredescribed in Example 231 from(1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate (step 5 of Example 260).

[2562]¹H-NMR (DMSO-d₆) δ: 11.93 (1H, br.s), 8.90 (1H, d, J=1.8 Hz), 8.63(1H, d, J=1.8 Hz), 7.76 (2H, d, J=8.4 Hz), 7.38-7.29 (8H, m), 7.11 (2H,d, J=8.4 Hz), 4.96-4.87 (1H, m), 2.90-2.79 (4H, m), 2.32 (3H, s), 2.27(3H, s), 1.26 (3H, t, J=7.5 Hz), 1.12 (3H, d, J=6.2 Hz).

[2563] MS (ESI) m/z: 521 [(MH)⁺], 519 [(M−H)⁻].

[2564] [α]²⁴ _(D) −8.17-(c 1.020, methanol)

Example 2622-{4-[6-Chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamatemono-p-toluenesulfonate

[2565] Step 1.2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1h-benzimidazol-1-yl]phenyl}ethanol

[2566] A mixture of2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol(1.83 g, 5.54 mmol), 2-pyridinecarboxaldehyde (0.53 ml, 5.54 mmol), andEtOH (40 ml) was refluxed for 1 hour. After cooling to room temperature,the solvent was removed. The residue was dissolved with benzene (50 ml)and treated with Pb(OAc)₄ (3.38 g, 6.10 mmol) at room temperature for 1hour. The mixture was diluted with EtOAc and the solution was washedwith sat. NaHCO₃ aq. and brine. The organic fraction was dried overMgSO₄, then filtered. After evaporation in vacuo, the residue waspurified by silica-gel column chromatography eluting withhexane/EtOAc=5/2 to afford 1.20 g (52%) of the title compound.

[2567]¹H-NMR (CDCl₃) δ: 8.42-8.39 (1H, m), 8.23 (1H, s), 8.10-8.07 (1H,m), 7.79-7.75 (1H, m), 7.40-7.23 (6H, m), 3.97 (2H, t, J=6.6 Hz), 2.99(2H, t, J=6.6 Hz)

[2568] MS (ES1) m/z: 418 ([M+H]⁺), 476 ([M+CF₃CO₂]⁻)

[2569] Step 2.2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1h-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[2570] The title compound was prepared according to the proceduredescribed in example 3 from2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol.

[2571]¹H-NMR (CDCl₃) δ: 8.39-8.37 (1H, m), 8.23 (1H, s), 8.10-8.06 (1H,m), 7.92-7.87 (2H, m), 7.81-7.76 (1H, m), 7.33-7.18 (8H, m), 4.35 (2H,t, J=6.8 Hz), 2.98 (2H, t, J=6.8 Hz), 2.41 (3H, s).

[2572] MS (ESI) m/z: 615 ([M+H]⁺), 613 ([M−H]⁻).

Example 2632-{4-[6-Chloro-2-(2-pyridin)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamatemono-p-toluenesulfonate

[2573] The title compound was prepared according to the proceduredescribed in Example 231 from2-(4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate.

[2574] MS (ESI) m/z: 615 ([M+H]⁺).

Example 264N-{[(2-{4-[6-Chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}4-methylbenzenesulfonamidemono-p-toluenesulfonate

[2575] Step 1.6-chloro-1-[4-(2-chloroethyl)phenyl]-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole

[2576] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 1 of Example 262).

[2577]¹H-NMR (CDCl₃) δ: 8.41-8.39 (1H, m), 8.24 (1H, s), 8.11 (1H, d,J=8.8 Hz), 7.82-7.76 (1H, m), 7.38 (2H, d, J=8.4 Hz), 7.35 (1H, s),7.30-7.25 (3H, m), 3.31 (2H, t, J=7.2 Hz), 3.19 (2H, t, J=7.2 Hz).

[2578] Step 2.1-[4-(2-azidoethyl)phenyl]-6-chloro-2-(2-1)yridinyl)-5-(trifluoromethyl)-1H-benzimidazole

[2579] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from6-chloro-1-[4-(2-chloroethyl)phenyl]-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole(step 1).

[2580]¹H-NMR (CDCl₃) δ: 8.40-8.39 (1H, m), 8.24 (1H, s), 8.10 (1H, d,J=7.9 Hz), 7.81-7.75 (1H, m), 7.39 (2H, d, J=8.4 Hz), 7.34 (1H, s),7.29-7.25 (3H, m), 3.61 (2H, t, J=6.8 Hz), 3.01 (2H, t, J=6.8 Hz).

[2581] Step 3.2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylamine

[2582] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole(step 2).

[2583]¹H-NMR (CDCl₃) δ: 8.37-8.36 (1H, m), 8.19 (1H, s), 8.03-8.00 (1H,m), 7.78-7.71 (1H, m), 7.32-7.18 (6H, m), 3.02 (2H, t, J=6.8 Hz), 2.82(2H, t, J=6.8 Hz), 2.17 (2H, br.s).

[2584] Step 4.N-{[(2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[2585] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylamine(step 3).

[2586]¹H-NMR (CDCl₃) δ: 8.42-8.39 (1H, m), 8.24 (1H, s), 8.10 (1H, d,J=8.1 Hz), 7.81-7.75 (1H, m), 7.69 (2H, d, J=8.3 Hz), 7.33-7.24 (8H, m),6.72-6.69 (1H, m), 3.63-3.56 (2H, m), 2.93 (2H, t, J=6.8 Hz), 2.38 (3H,s).

[2587] MS (ESI) m/z: 614 [(MH)⁺], 612 [(M−H)⁻].

[2588] Step 5.N-[(2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamidemono-p-toluenesulfonate

[2589] The title compound was prepared according to the proceduredescribed in Example 231 fromN-{[(2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(step 4).

[2590]¹H-NMR (DMSO-d₆) δ: 10.63 (1H, br.s), 8.41-8.39 (1H, m), 8.35 (1H,s), 8.08-7.95 (2H, m), 7.75 (2H, d, J=8.3 Hz), 7.49 (2H, d, J=8.3 Hz),7.44-7.27 (8H, m), 7.10 (2H, d, J=7.7 Hz), 6.61-6.57 (1H, m), 3.30-3.23(2H, m), 2.74 (2H, t, J=7.0 Hz), 2.31 (3H, s), 2.27 (3H, s).

[2591] MS (ESI) m/z: 614 [(MH)⁺], 612 [(M−H)⁻].

Example 265N-}[(2-{4-[6-Chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamidemono-p-toluenesulfonate

[2592] Step 1.6-chloro-1-[4-(2-chloroethyl)phenyl]-2-(1H-Pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazole

[2593] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 1, Example 255).

[2594]¹H-NMR (DMSO-d6) δ:13.29 (1H, s), 8.25 (1H, s), 7.83-7.81 (1H, m),7.52-7.43 (4H, m), 7.23 (1H, s), 6.67-6.65 (1H, m), 3.95 (2H, t, J=7.0Hz), 3.16 (2H, t, J=7.0 Hz).

[2595] Step 2.1-[4-(2-azidoethyl)phenyl-6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazole

[2596] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from6-chloro-1-[4-(2-chloroethyl)phenyl]-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazole(step 1). ¹H-NMR (DMSO-d6) δ: 13.27 (1H, s), 8.25 (1H, s), 7.82 (1H, s),7.52-7.43 (4H, m), 7.21 (1H, s), 6.65 (1H, s), 3.67 (2H, t, J=7.0 Hz),2.99 (2H, t, J=7.0 Hz).

[2597] Step 3.2-4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylamine

[2598] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl-6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazole(step 2).

[2599] MS (EI) m/z: 405 (M⁺).

[2600] Step 4.N-{[(2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[2601] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylamine(step 3).

[2602]¹H-NMR (CDCl₃) δ: 8.17 (1H, s), 7.69 (2H, d, J=8.4 Hz), 7.57 (1H,d, J=2.2 Hz), 7.30-7.18 (8H, m), 6.82-6.77 (1H, m), 6.60 (1H, d, J=2.2Hz), 3.64-3.58 (2H, m), 2.91 (2H, t, J=6.4 Hz), 2.39 (3H, s).

[2603] Step 5.N-{[(2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamidemono-p-toluenesulfonate

[2604] The title compound was prepared according to the proceduredescribed in Example 231 fromN-{[(2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(step 4).

[2605]¹H-NMR (DMSO-d₆) 8:10.64 (1H, br.s), 8.24 (1H, s), 8.35 (1H, s),7.78-7.75 (3H, m), 7.49-7.80 (8H, m), 7.11 (2H, d, J=7.9 Hz), 6.60-6.57(1H, m), 6.38-6.37 (1H, m), 3.33-3.26 (2H, m), 2.78 (2H, t, J=7.2 Hz),2.32 (3H, s), 2.28 (3H, s).

[2606] MS (ESI) m/z: 603 [(MH)⁺], 601 [(M−H)⁻].

Example 2663-(3-Chloro-4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2607] Step 1. diethyl 2-(2-chloro-4-nitroiphenyl)malonate

[2608] Diethylmalonate (5.2 ml, 34.2 mmol) was added to the suspensionof NaH (1.4 g, 34.2 mmol) in 80 ml of 1,4-dioxane followed by thesuccessive addition of CuBr (4.9 g, 34.2 mmol) and3-chloro-4-fluoronitrobenzene (5.0 g, 28.5 mmol). The mixture wasstirred at room temperature for 0.5 h and under reflux temperature for12 h. The mixture was poured into water, and the precipitate wasfiltered off through a pad of celite. The filtrate was extracted withethyl acetate (2×50 ml). The organic layer was washed with brine, dried(MgSO₄), and concentrated to give a green oil. This mixture was purifiedby SiO2 column chromatography developing with hexane/ethyl acetate(10/1) gave 7.6 g (85%) of the title compound as yellow oil

[2609]¹H-NMR (CDCl₃) δ: 8.30 (1H, d, J=2.4 Hz), 8.16 (1H, dd, J=2.2, 8.6Hz), 7.74 (1H, d, J=8.6 Hz), 5.27 (1H, s), 4.28 (2H, q, J=7.2 Hz), 4.27(2H, q, J=7.2 Hz), 1.29 (6H, t, J=7.2 Hz).

[2610] Step 2. 2-(2-chloro-4-nitrophenyl)acetic acid

[2611] To a solution of diethyl 2-(2-chloro-4-nitrophenyl)malonate (step1, 7.6 g, 24.2 mmol) in methanol (18 ml) was added 6M-NaOH (12 ml) andstirred for 1 h at 50° C. The reaction was quenched by the addition ofsaturated citric acid aqueous solution (16 ml) and water. The organiclayer was extracted with ethyl acetate (2×50 ml), washed with brine,dried (MgSO₄) and concentrated to give 4.52 g (87%) of title compound aslight yellow solid.

[2612]¹H-NMR (CDCl₃) δ: 12.6 (1H, br.s), 8.30 (1H, d, J=2.6 Hz), 8.18(1H, dd, J=2.4, 8.4 Hz), 7.73 (1H, d, J=8.6 Hz), 3.90 (2H, s).

[2613] Step 3. methyl 2-(2-chloro-4-nitrophenyl)acetate

[2614] To a solution of 2-(2-chloro-4-nitrophenyl)acetic acid (step 2,4.5 g, 21 mmol) in dimethyl acetate/methanol (4/1) was addedtrimethylsillylchloride (0.3 ml) and stirred for 7 h at roomtemperature. The solvent was removed and the residue was purified bySiO₂ column chromatography with developing hexane/ethyl acetate (10/1)to give 3.6 g (74%) of title compound as yellow oil.

[2615]¹H-NMR (CDCl₃) δ: 8.28 (1H, d, J=2.3 Hz), 8.11 (1H, dd, J=2.3, 8.6Hz), 7.50 (1H, d, J=8.6 Hz), 3.88 (2H, s), 3.74 (3H, s).

[2616] Step 4. methyl 2-(4-amino-2-chlorophenyl)acetate

[2617] To a solution of methyl 2-(2-chloro-4-nitrophenyl)acetate (step3, 3.6 g, 15.6 mmol) in ethanol/water (4/1) were added Fe (4.4 g, 78.0mmol) and NH₄Cl (409 mg, 7.8 mmol). The mixture was stirred for 1 hunder reflux temperature. The solvent was removed and the residue wasdiluted with CH₂Cl₂.The mixture was washed with brine, dried (MgSO₄) andconcentrated to give 2.59 g (83%) of title compound as orange oil.

[2618] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from methyl{2-(2-chloro-4-nitrophenyl)acetate (step 3)

[2619]¹H-NMR (CDCl₃) δ: 7.04 (1H, d, J=8.2 Hz), 6.72 (1H, d, J=2.3 Hz),6.54 (1H, dd, J=2.5, 8.2 Hz), 3.70 (3H, s), 3.66 (2H, s).

[2620] Step 5. methyl{2-chloro-4-[(-4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}acetate

[2621] To a mixture of methyl 2-(4-amino-2-chlorophenyl)acetate (step 4,2.6 g, 13.0 mmol) and 4,6-Dimethyl-3-nitro-2-pyridine (step 2 of Example1, 2.4 g, 13.0 mmol) in DMSO was added diisopropylethylamine. Theresulting mixture was stirred for 9 h at 50° C. To the mixture waspoured into water and extracted with ethyl acetate (3×30 ml). Theorganic layer was washed with brine, dried (MgSO₄) and concentrated togive a brown oil. This was purified by SiO₂ column chromatography withdeveloping hexane/ethyl acetate (10/1) to give 1.4 g (29%) of titlecompound as yellow solid.

[2622]¹H-NMR (CDCl₃) δ: 9.55 (1H, br.s), 7.90 (1H, d, J=2.2 Hz), 7.43(1H, dd, J=2.2, 8.3 Hz), 7.24 (1H, d, J=8.3 Hz), 6.59 (1H, s), 3.76 (2H,s), 3.72 (3H, s), 2.56 (3H, s), 2.46 (3H, s).

[2623] MS (EI) m/z: 349 (M⁺).

[2624] Step 6. methyl2-chloro-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}acetate

[2625] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 frommethyl{2-chloro-4-[(-4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}acetate (step 5)

[2626]¹H-NMR (CDCl₃) δ: 7.26 (1H, d, J=2.2 Hz), 7.20 (1H, d, J=8.3 Hz),7.00 (1H, dd, J=2.2, 8.3 Hz), 6.64 (1H, s), 6.37 (1H, br.s), 3.70 (3H,s), 3.27 (1H, br.s), 2.68 (3H, s), 2.38 (3H, s), 2.20 (3H, s).

[2627] Step 7. methyl2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenylethylacetate

[2628] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from methyl2-chloro-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl)}acetate(step 6)

[2629]¹H-NMR (CDCl₃) δ: 7.50 (1H, d, 8.3 Hz), 7.47 (1H, d, J=2.2 Hz),7.31 (1H, dd, J=2.2, 8.3 Hz), 6.92 (1H, s), 3.87 (2H, s), 3.77 (3H, s),2.85 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.53 (3H, s), 1.31 (3H, t, J=7.5Hz).

[2630] MS (EI) m/z: 357 (M⁺).

[2631] Step 8.2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenylethanol

[2632] To a solution of methyl2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenylethylacetate (step 7, 1.13 g, 3.15 mmol) was added carefully LAH and stirredfor 1 h at room temperature. The reaction was quenched with water andthe mixture was diluted with ethyl acetate (50 ml). To this mixture wasadded saturated potassium sodium tartarate aqueous solution (50 ml) andstirred for 2.5 h. The organic layer was separated and aqueous layer wasextracted with ethyl acetate (2×20 ml). The combined organic layer waswashed with brine, dried (Mg2SO4) and concentrated to give 1.0 g oftitle compound as white solid.

[2633]¹H-NMR (CDCl₃) δ: 7.41-7.53 (2H, m), 7.25-7.29 (1H, m), 6.92 (1H,s), 3.96 (2H, m), 3.11 (3H, t, J=7.4 Hz), 2.82 (2H, m), 2.65 (3H, s),2.53 (3H, s), 1.30 (3H, t, J=7.4 Hz).

[2634] MS (EI) m/z: 329 (M⁺).

[2635] Step 9.3-[3-chloro-4-(2-chloroethyl)phenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2636] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from methyl2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenylethanol(step 8)

[2637]¹H-NMR (CDCl₃) δ: 7.45-7.52 (2H, m), 7.23-7.31 (1H, m), 6.92 (1H,s), 3.82 (2H, t, J=7.3 Hz), 3.29 (2H, t, J=7.3 Hz), 2.83 (2H, q, J=7.6Hz), 2.65 (3H, s), 2.53 (3H, s), 1.30 (3H, t, J=7.6 Hz).

[2638] Step 10.3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2639] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from3-[3-chloro-4-(2-chloroethyl)phenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 9)

[2640]¹H-NMR (CDCl₃) δ: 7.45-7.48 (2H, m), 7.29 (1H, dd, J=2.1, 7.9 Hz),6.92 (1H, s), 3.62 (1H, t, J=7.1 Hz), 3.12 (1H, t, J=7.3 Hz), 2.83 (2H,q, J=7.4 Hz), 2.65 (3H, s), 2.53 (3H, s), 1.30 (3H, t, J=7.4 Hz).

[2641] Step 11.2-[2-chloro-4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanamine

[2642] To a solution of methyl3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 10, 430 mg, 1.2 mmol) in ethanol/water (4/1) were added Fe (335mg, 6.0 mmol) and NH₄Cl (409 mg, 7.8 mmol). The mixture was stirred for1 h under reflux temperature. The solvent was removed and the residuewas diluted with CH₂Cl₂. The mixture was washed with brine, dried(MgSO₄) and concentrated to give 390 mg of title compound as orange oil.

[2643]¹H-NMR (CDCl₃) δ: 7.44 (2H, d, J=7.4 Hz), 7.25 (1H, m), 6.92 (1H,s), 2.92-3.15 (6H, m), 2.83 (2H, q, J=7.4 Hz), 2.65 (3H, s), 2.53 (3H,s), 1.30 (3H, t, J=7.4 Hz).

[2644] Step 12.2-[2-chloro-4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanamine

[2645] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[2-chloro-4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanamine(Step 11)

[2646]¹H-NMR (CDCl₃) δ: 7.83 (2H, d, J=8.4 Hz), 7.28-7.36 (4H, m), 7.14(1H, d, J=7.7 Hz), 6.92 (1H, s), 6.28 (1H, br.s), 3.58 (2H, dt, J=6.3Hz), 3.02 (2H, t, J=6.4 Hz), 2.74 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.45(3H, s), 2.41 (3H, s), 1.25 (3H, t, J=7.6 Hz).

[2647] MS (ESI) m/z: 526 (M⁺).

Example 2673-(2-Chloro-4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2648] Step 1.2-{3-chloro-4-[(-4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

[2649] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 4,6-Dimethyl-3-nitro-2-pyridine(0.66 g, 3.8 mmol, step 2 of Example 1) and4-amino-2-chloro-phenylethanol (0.72 g, 3.8 mmol, Eur. J. Med. Chem.,1996, 31, 133.).

[2650]¹H-NMR (CDCl₃) δ: 9.85 (1H, s), 8.37 (1H, d, J=8.4 Hz), 7.31 (1H,d, J=2.0 Hz), 7.14 (1H, dd, J=2.0, 8.3 Hz), 6.60 (1H, s), 3.87 (2H, dt,J=6.2, 6.4 Hz), 2.84 (2H, t, J=6.4 Hz), 2.56 (3H, s), 2.46 (3H, s), 1.40(1H, t, J=6.2 Hz).

[2651] MS (EI) m/z: 321 (M⁺).

[2652] Step 2. methyl3-chloro-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol

[2653] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{3-chloro-4-[(-4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol(step 1).

[2654]¹H-NMR (CDCl₃) δ: 7.26 (1H, d, J=2.2 Hz), 7.20 (1H, d, J=8.3 Hz),7.00 (1H, dd, J=2.2, 8.3 Hz), 6.64 (1H, s), 6.37 (1H, br.s), 3.70 (3H,s), 3.27 (1H, br.s), 2.68 (3H, s), 2.38 (3H, s), 2.20 (3H, s).

[2655] Step 3.2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenylethylpropionate

[2656] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from3-chloro-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethylpropionate (step 2).

[2657]¹H-NMR (CDCl₃) δ: 7.50 (1H, d, 8.3 Hz), 7.47 (1H, d, J=2.2 Hz),7.31 (1H, dd, J=2.2, 8.3 Hz), 6.92 (1H, s), 3.87 (2H, s), 3.77 (3H, s),2.85 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.53 (3H, s), 1.31 (3H, t, J=7.5Hz).

[2658] MS (E1) m/z: 357 (M⁺).

[2659] Step 4.2-[3-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenylethanol

[2660] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from methyl2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenylethyl propionate (step 3).

[2661]¹H-NMR (CDCl₃) δ: 7.51 (1H, s), 7.34 (2H, s), 6.91 (1H, s), 3.96(2H, dd, J=6.2, 12.0 Hz), 2.96 (2H, t, J=7.4 Hz), 2.70 (2H, m), 2.66(3H, s), 2.51 (3H, s), 1.67 (1H, br.t, J=6.2 Hz), 1.28 (3H, t, J=7.4Hz).

[2662] MS (ESI) m/z: 329 (M⁺).

[2663] Step 5.3-[2-chloro-4-(2-chloroethyl)phenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2664] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-3-[chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenylethanol(step 4).

[2665]¹H-NMR (CDCl₃) δ: 7.49 (1H, d, J=1.3 Hz), 7.34-7.49 (2H, m), 6.91(1H, s), 3.80 (2H, t, J=7.2 Hz), 3.17 (2H, t, J=7.0 Hz), 2.60-2.85 (2H,m), 2.66 (3H, s), 2.51 (3H, s), 1.28 (3H, t, J=7.5 Hz).

[2666] MS (EI) m/z: 347 [(M−H)⁻].

[2667] Step 6.3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2668] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from3-[2-chloro-4-(2-chloroethyl)phenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 5).

[2669]¹H-NMR (CDCl₃) δ: 7.49 (1H, m, J=1.8 Hz), 7.31-7.38 (2H, m), 6.91(1H, s), 3.62 (2H, t, J=7.0 Hz), 2.98 (2H, t, J=7.3 Hz), 2.60-2.80 (2H,m), 2.66 (3H, s), 2.51 (3H, s), 1.27 (3H, t, J=7.5 Hz).

[2670] MS (EI) m/z: 354 (M⁺).

[2671] Step 7.2-[3-chloro-4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanamine

[2672] To a stirred solution of3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 6, 149 mg, 0.4 mmol) in THF (4 ml) was added triphenylphosphine(116 mg, 0.4 mmol) at room temperature. After completion of theaddition, the stirring was continued for an additional 2.5 h at the sametemperature and 3.5 h under reflux temperature. To the resulting mixturewas added H₂O (1.0 ml) at room temperature, and the solvent was removed.The mixture was dissolved in CH₂Cl₂ (100 ml), washed with brine. TheOrganic layer was dried (MgSO₄), and concentrated to give a yellow oil.

[2673] MS (EI) m/z: 328 (M⁺).

[2674] Step 8.2-[3-chloro-4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanamine

[2675] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[3-chloro-4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanamine(step 7).

[2676]¹H-NMR (CDCl₃) δ: 7.88 (1H, s), 7.85 (1H, s), 7.19-7.34 (5H, m),6.92 (1H, s), 6.94 (1H, s), 6.13 (1H, br.s), 3.54 (2H, m), 2.78 (2H, t,J=6.4 Hz), 2.67 (3H, s), 2.63 (3H, m), 2.42 (3H, s), 2.40 (3H, s), 1.25(3H, t, J=7.5 Hz).

[2677] MS (EI) m/z: 526 (M⁺).

Example 2682-Ethyl-3-(3-methoxy-4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2678] Step 1. diethyl 2-(2-methoxy-4-nitrophenyl)malonate

[2679] The title compound was prepared according to the proceduredescribed in step 1 of Example 266 from 4-bromo-3-methoxynitrobenzene.

[2680]¹H-NMR (CDCl₃) δ: 7.78 (1H, dd, J=2.2, 8.4 Hz), 7.75 (1H, d, J=2.2Hz), 7.54 (1H, d, J=8.4 Hz), 5.15 (1H, s), 4.25 (2H, q, J=7.2 Hz), 4.25(2H, q, J=7.2 Hz), 3.94 (3H, s), 1.28 (6H, t, J=7.2 Hz).

[2681] Step 2. 2-(2-methoxy-4-nitrophenyl)acetic acid

[2682] The title compound was prepared according to the proceduredescribed in step 2 of Example 266 from diethyl2-(2-methoxy-4-nitrophenyl)malonate (step 1).

[2683]¹H-NMR (CDCl₃) δ: 12.4 (1H, br.s), 7.82 (1H, dd, J=2.2, 8.4 Hz),7.75 (1H, dd, J=2.2 Hz), 7.50 (1H, d, J=8.4 Hz), 3.90 (3H, s), 3.66 (2H,s).

[2684] Step 3. methyl 2-(2-methoxy-4-nitrophenyl)acetate

[2685] To a solution of 2-(2-methoxy-4-nitrophenyl)acetic acid (step 2,1.2 g, 5.5 mmol) in methanol/dichloromethane (11 ml, 1/1) was addedtrimethylsillyldiazomethane (2 M, 5.6 ml, 11.8 mmol) and stirred for 10min at room temperature. The mixture was quenched with saturated citricacid aqueous solution and the extracted with ethyl acetate (3×20 ml).The organic layer was washed with brine, dried (MgSO₄) and concentratedto give 1.2 g of title compound as orange solid.

[2686]¹H-NMR (CDCl₃) δ: 7.83 (1H, dd, J=2.2, 8.3 Hz), 7.73 (1H, dd,J=2.2 Hz), 7.34 (1H, d, J=8.1 Hz), 3.93 (3H, s), 3.71 (2H, s), 3.71 (3H,s).

[2687] Step 4. methyl 2-(4-amino-2-methoxylphenyl)acetate

[2688] To a solution of methyl 2-(2-methoxy-4-nitrophenyl) acetate (step3, 1.2 g, 5.5 mmol) in methanol (10 ml) was added 10% Pd/C (130 mg, 0.12mmol) and stirred under hydrogen atmosphere for 3 h at room temperature.The catalyst was filtered off through a pad of celite and well washedwith ethanol and ethyl acetate. The filtrate was concentrated to give1.1 g of title compound as pink oil.

[2689]¹H-NMR (CDCl₃) δ: 6.94 (1H, d, J=7.7 Hz), 6.26 (1H, d, J=2.0 Hz),6.23 (1H, s), 3.70 (3H, s), 3.76 (3H, s), 3.67 (3H, s), 3.52 (2H, s).

[2690] Step 5.methyl{4-[(-4,6-dimethyl-3-nitro-2-pyridinyl)amino]-2-methoxyphenyl}acetate

[2691] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from methyl 2-(4-amino-2-methoxyphenyl)acetate (step 4).

[2692]¹H-NMR (CDCl₃) δ: 9.60 (1H, s), 7.47 (1H, d, J=1.7 Hz), 7.06-7.15(2H, m), 6.55 (1H, s), 3.84 (3H, s), 3.69 (3H, s), 3.62 (2H, s), 2.56(3H, s), 2.44 (3H, s).

[2693] MS (EI) m/z: 345 (M⁺).

[2694] Step 6. methyl{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]-2-methoxyphenyl}acetate

[2695] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 frommethyl{4-[(-4,6-dimethyl-3-nitro-2-pyridinyl)amino]-2-methoxyphenyl}acetate(step 5).

[2696]¹H-NMR (CDCl₃) δ: 7.03 (1H, d, J=5.1 Hz), 7.02 (1H, s), 6.60 (1H,s), 6.57 (1H, dd, J=2.2, 8.3 Hz), 3.79 (3H, s), 3.68 (3H, s), 3.56 (2H,s), 3.25-3.35(br.s, 2H), 2.38 (3H, s), 2.20 (3H, s).

[2697] MS (EI) m/z: 315 (M⁺).

[2698] Step 7. methyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methoxymhenylethylacetate

[2699] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 frommethyl{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]-2-methoxyphenyl}acetate(step 6).

[2700]¹H-NMR (CDCl₃) δ: 7.36 (1H, d, J=7.9 Hz), 6.89-6.99 (3H, m), 3.84(2H, s), 3.74 (3H, s), 3.71 (2H, s), 2.85 (2H, q, J=7.5 Hz), 2.66 (3H,s), 2.53 (3H, s), 1.30 (3H, t, J=7.5 Hz).

[2701] MS (EI) m/z: 353 (M⁺).

[2702] Step 8.2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methoxyphenylethanol

[2703] The title compound was prepared according to the proceduredescribed in step 8 of Example 266 from methyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methoxyphenylethylacetate (step 7).

[2704]¹H-NMR (CDCl₃) δ: 7.33 (1H, d, J=7.7 Hz), 6.87-6.95 (3H, m), 3.90(2H, dt, J=6.0, 6.2 Hz), 3.84 (3H, s), 2.98(2H, t, J=6.4 Hz), 2.84(2H,q, J=7.5 Hz), 2.66 (3H, s), 2.53 (3H, s), 1.76 (1H, br.t), 1.30 (3H, t,J=7.5 Hz).

[2705] MS (EI) m/z: 324 [(M−H)⁻].

[2706] Step 9.3-[4-(2-chloroethyl)-3-methoxyphenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2707] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methoxyphenylethanol(step 8).

[2708]¹H-NMR (CDCl₃) δ: 7.33 (11H, d, J=7.7 Hz), 6.87-6.94 (3H, m), 3.84(3H, s), 3.77 (3H, t, J=7.6 Hz), 3.16 (2H, t, J=7.3 Hz), 2.84 (2H, q,J=7.6 Hz), 2.66 (3H, s), 2.53 (3H, s), 1.30 (3H, t, J=7.6 Hz).

[2709] Step 10.3-04-(2-azidoethyl)-3-methoxyphenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2710] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from3-[4-(2-chloroethyl)-3-methoxyphenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 9).

[2711]¹H-NMR (CDCl₃) δ: 7.45-7.48 (2H, m), 7.29 (1H, dd, J=2.1, 7.9 Hz),6.92 (1H, s), 3.62 (1H, t, 37.1 Hz), 3.12 (1H, t, J=7.3 Hz), 2.83 (2H,q, J=7.4 Hz), 2.65 (3H, s), 2.53 (3H, s), 1.30 (3H, t, J=7.4 Hz).

[2712] Step 11.2-[4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl-2-methoxy)phenyl]ethanamine

[2713] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from3-[4-(2-azidoethyl)-3-methoxyphenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 10).

[2714]¹H-NMR (CDCl₃) δ: 7.30 (1H, d, J=7.7 Hz), 6.92 (1H, dd, J=2.0, 7.9Hz), 6.91 (1H, br.s), 6.86 (1H, d, J=2.0 Hz), 3.83 (3H, s), 2.65 (3H,s), 2.99 (2H, br.t, J=4.5 Hz), 2.85 (2H, q, J=8.3 Hz), 2.84 (2H, q,J=7.7 Hz), 2.66 (3H, s), 2.53 (3H, s), 1.29 (3H, t, J=7.7 Hz).

[2715] Step 12.2-ethyl-(3-methoxy-4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2716] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl-2-methoxy)phenyl]ethanamine(step 11).

[2717]¹H-NMR (CDCl₃) δ: 7.86 (2H, d, J=8.3 Hz), 7.30 (4H, m), 7.14 (1H,d, J=8.1 Hz), 7.01 (1H, d, J=7.9 Hz), 6.92 (1H, s), 6.79 (1H, d, J=2.0Hz), 6.63 (1H, dd, J=1.8, 7.7 Hz), 6.04 (1H, br.t, J=5.1 Hz), 3.74 (3H,s), 3.51 (2H, dt, J=6.0 Hz), 2.85 (2H, t, J=6.2 Hz), 2.70 (2H, q, J=7.5Hz), 2.66 (3H, s), 2.44 (3H, s), 2.41 (3H, s), 1.23 (3H, t, J=7.5 Hz).

[2718] MS (ESI) m/z: 522 [(M+H)⁺], 520 [(M−H)⁻].

Example 2692-Ethyl-3-(3-methyl-4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2719] Step 1. diethyl 2-(2-methyl-4-nitrophenyl)malonate

[2720] The title compound was prepared according to the proceduredescribed in step 1 of Example 268 from 4-bromo-3-methylnitrobenzene.

[2721]¹H-NMR (CDCl₃) δ: 8.10 (1H, s), 8.05-8.10 (1H, m), 7.62 (1H, d,J=9.2 Hz, 4.93 (1H, s), 4.26 (2H, q, J=7.3 Hz), 4.25 (2H, q, J=7.3 Hz),2.46 (3H, s), 1.28 (6H, t, J=7.3 Hz).

[2722] Step 2. 2-(2-methyl-4-nitrophenyl)acetic acid

[2723] The title compound was prepared according to the proceduredescribed in step 2 of Example 266 from diethyl2-(2-methyl-4-nitrophenyl) malonate (step 1)

[2724]¹H-NMR (CDCl₃) δ: 8.08 (1H, br.s), 8.02 (1H, dd, J=8.6 Hz), 7.49(1H, d, J=8.4 Hz), 3.77 (2H, s), 2.35 (3H, s).

[2725] Step 3. methyl 2-(2-methyl-4-nitrophenyl)acetate

[2726] The title compound was prepared according to the proceduredescribed in step 3 of Example 266 from 2-(2-methyl-4-nitrophenyl)aceticacid (step 2).

[2727]¹H-NMR (CDCl₃) δ: 8.07 (1H, d, J=2.1 Hz), 8.02 (1H, dd, J=2.3, 5.9Hz), 7.36 (1H, d, J=8.4 Hz), 3.74 (2H, s), 3.71 (3H, s), 2.42 (3H, s).

[2728] Step 4. methyl 2-(4-amino-2-methylphenyl)acetate

[2729] The title compound was prepared according to the proceduredescribed in step 4 of Example 268 from methyl2-(2-methyl-4-nitrophenyl)acetate (step 3)

[2730]¹H-NMR (CDCl₃) δ: 6.97 (1H, d, J=7.9 Hz), 6.48-6.52 (2H, m), 3.67(3H, s), 3.57 (2H, br.s), 3.53 (3H, s), 2.22 (3H, s).

[2731] Step 5. methyl{4-[(-4,6-dimethyl-3-nitro-2-pyridinyl)amino]-2-methylphenyl}acetate

[2732] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from methyl 2-(4-amino-2-methylphenyl)acetate (step 4).

[2733]¹H-NMR (CDCl₃) δ: 7.54 (1H, br.d, J=8.3 Hz), 7.38 (1H, br.s), 7.17(1H, d, J=8.39 Hz), 6.52 (1H, s), 3.69 (3H, s), 3.63 (2H, s), 2.55 (3H,s), 2.43 (3H, s), 2.32 (3H, s).

[2734] MS (EI) m/z: 345 (M⁺).

[2735] Step 6. methyl{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]-2-methyl]phenyl}acetate

[2736] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 frommethyl{4-[(-4,6-dimethyl-3-nitro-2-pyridinyl)amino]-2-methylphenyl}acetate(step 5).

[2737]¹H-NMR (CDCl₃) δ: 7.07 (1H, d, J=9.0 Hz), 6.91-6.93 (2H, m), 6.62(1H, s), 6.36 (1H, br.s), 3.79 (3H, s), 3.67 (3H, s), 3.57 (2H, s), 3.30(br.s, 2H), 2.37 (3H, s), 2.26 (3H, s), 2.2 (3H, s).

[2738] Step 7. methyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylphenylethylacetate

[2739] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 frommethyl{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]-2-methylphenyl}acetate(step 6).

[2740]¹H-NMR (CDCl₃) δ: 7.39 (1H, d, J=7.6 Hz), 7.17-7.25 (2H, m), 6.90(1H, s), 3.74 (3H, s), 3.72 (2H, s), 2.82 (2H, q, J=7.4 Hz), 2.65 (3H,s), 2.52 (3H, s), 2.40 (3H, s), 1.28 (3H, t, J=7.6 Hz).

[2741] MS (EI) m/z: 337 (M⁺).

[2742] Step 8.2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylphenylethanol

[2743] The title compound was prepared according to the proceduredescribed in step 8 of Example 266 from methyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylphenylethylacetate (step 7).

[2744]¹H-NMR (CDCl₃) δ: 7.35 (1H, d, J=7.9 Hz), 7.17 (1H, s), 7.16 (1H,d, J=7.9 Hz), 6.90 (1H, s), 3.84 (2H, dt, J=6.8 Hz), 2.96 (2H, t, J=7.0Hz), 2.81 (2H, q, J=7.5 Hz), 2.66 (3H, s), 2.52 (3H, s), 2.40 (s, 3H),1.91 (1H, br.t), 1.28 (3H, t, J=7.5 Hz).

[2745] MS (EI) m/z: 324 [(M−H)⁻].

[2746] Step 9.3-[4-(2-chloroethyl)-3-methylpheny-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2747] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylphenylethanol(step 8).

[2748]¹H-NMR (CDCl₃) δ: 7.35 (1H, d, J=8.4 Hz), 7.17-7.19 (2H, m), 6.90(1H, s), 3.75 (2H, t, J=7.6 Hz), 3.17 (2H, t, J=7.6 Hz), 2.81 (2H, q,J=7.5 Hz), 2.65 (3H, s), 2.41 (3H, s), 2.36 (3H, s), 1.28 (3H, t, J=7.5Hz).

[2749] Step 10.3-[4-(2-azidoethyl)-3-methylphenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2750] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from3-[4-(2-chloroethyl)-3-methylphenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 9).

[2751]¹H-NMR (CDCl₃) δ: 7.34 (1H, d, J=8.7 Hz), 7.19-7.26 (2H, m), 6.90(1H, s), 3.62 (1H, t, J=7.1 Hz), 3.56 (2H, t, J=7.6 Hz), 2.99 (2H, t,J=7.6 Hz), 2.81 (2H, q, J=7.6 Hz), 2.65 (3H, s), 2.52 (3H, s), 2.41 (3H,s), 1.27 (3H, t, J=7.6 Hz).

[2752] Step 11.2-[4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl-2-methyl)phenyl]ethanamine

[2753] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from3-[4-(2-azidoethyl)-3-methylphenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 10).

[2754]¹H-NMR (CDCl₃) δ: 7.32 (1H, d, J=7.7 Hz), 7.14-7.16 (2H, m), 6.91(1H, br.s), 6.90 (1H, s), 3.02 (2H, br.t, J=7.3 Hz), 2.77-2.87 (4H, m),2.65 (3H, s), 2.53 (3H, s), 2.40 (3H, s), 1.28 (3H, t, J=7.5 Hz).

[2755] Step 12.2-ethyl-(3-methyl-4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2756] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-[4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl-2-methyl)phenyl]ethanamine(step 11).

[2757]¹H-NMR (CDCl₃) δ: 7.86 (1H, d, J=8.0 Hz), 7.31 (1H, d, J=8.0 Hz),7.03 (1H, d, J=7.9 Hz), 6.91 (1H, s), 6.85 (1H, d, J=8.4 Hz), 6.07-6.11(1H, m), 3.51 (2H, q, J=6.4 Hz), 2.85 (2H, t, J=6.4 Hz), 261-2.69 (2H,m), 2.69 (3H, s), 2.44 (3H, s), 2.28 (3H, s), 1.23 (3H, t, J=7.5 Hz).

[2758] MS (ESI) m/z: 506 [(M+H)⁺], 504 [(M−H)⁻].

Example 2706-Chloro-2-ethyl-1-(6-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole

[2759] Step 1. (4-amino-2-pyridinyl)acetonitrile

[2760] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from (4-nitro-2-pyridinyl)acetonitrile(8.6 g, 52.9 mmol, Katz; R. B.; Voyle, M., Synthesis., 1989, 4, 314.).

[2761]¹H-NMR (CDCl₃) δ: 8.04 (1H, d, J=2.8 Hz), 7.17 (1H, d, J=8.2 Hz),6.99 (1H, dd, J=2.8, 8.4 Hz), 3.81 (2H, s), 3.76 (2H, br.s).

[2762] Step2.{5-[5-chloro-2-nitro-4-(trifluoromehyl)anilino]-2-pyridinyl}acetonitrile

[2763] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from (5-aminopyridine-2-yl)acetonitrile(step 1).

[2764]¹H-NMR (CDCl₃) δ: 9.66 (1H, s), 8.60 (2H, m), 7.71 (1H, dd, J=2.6,8.4 Hz), 7.60 (1H, d, J=8.3 Hz), 7.13 (1H, s), 4.03 (2H, s).

[2765] MS (EI) m/z: 356 (M⁺).

[2766] Step 3.{5-[2-amino-5-chloro-4-(trifluoromehyl)anilino]-2-pyridinyl}acetonitrile

[2767] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from{5-[5-chloro-2-nitro-4-(trifluoromehyl)anilino]-2-pyridinyl}acetonitrile(step 2).

[2768]¹H-NMR (CDCl₃) δ: 8.25 (1H, d, J=2.1 Hz), 7.12-7.34 (3H, m), 5.47(1H, br.s), 3.89 (2H, s), 3.78 (2H, br.s).

[2769] Step 4.{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}acetonitrile

[2770] The title compound was prepared according to the proceduredescribed in step 5 of Example 1from{5-[2-amino-5-chloro-4-(trifluoromehyl)anilino]-2-pyridinyl]acetonitrile(step 3).

[2771]¹H-NMR (CDCl₃) δ: 8.66 (1H, s), 8.15 (1H, s), 7.73-7.83 (2H, m),7.12 (1H, s), 4.12 (2H, s), 2.79 (2H, q, J=7.6 Hz), 1.40 (3H, t, J=7.6Hz).

[2772] Step 5.2-{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethanamine

[2773] To a solution of{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}acetonitrile(step 4, 1.0 g, 2.8 mmol), in ammonia-ethanol (30 ml) was added Raney-Niand stirred for 8 h under hydrogen atmosphere (3.0 kgf/cm²). Thecatalyst was filtered off and the solvent was removed. The residue wasdiluted with ethyl acetate, washed with brine, dried (MgSO₄) andconcentrated to give 813 mg of title compound as black solid.

[2774] MS (EI) m/z: 368 (M⁺).

[2775] Step 6.6-chloro-2-ethyl-1-(6-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl)}-3-pyridinyl)-5-(trifluoromehyl)-1H-benzimidazol

[2776] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethanamine(step 5).

[2777]¹H-NMR (CDCl₃) δ: 8.63 (1H, d, J=2.2 Hz), 8.14 (1H, s), 7.77 (2H,d, J=8.3 Hz), 7.66 (1H, dd, J=2.6, 8.3 Hz), 7.45 (1H, d, J=8.3 Hz), 7.30(2H, d, J=8.4 Hz), 7.21 (1H, s), 3.73-3.80 (2H, m), 3.17 (2H, t, J=6.2Hz), 2.79 (2H, q, J=7.5 Hz), 2.42 (3H, s), 1.38 (3H, t, J=7.5 Hz).

[2778] MS (ESI) m/z: 566 [(M+H)⁺], 564 [(M−H)⁻].

Example 2716-Chloro-2-ethyl-1-(6-2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazolesodium salt

[2779] The title compound was prepared according to the proceduredescribed in Example 2 from6-chloro-2-ethyl-1-(6-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-3-pyridinyl)-5-(trifluoromehyl)-1H-benzimidazol(Example 270).

[2780]¹H-NMR (DMSO-d₆) δ: 8.71 (1H, br.s), 8.20 (1H, br.s) 7.95 (1H, m),7.43-7.64 (4H, m), 7.12 (2H, br.s), 6.09 (1H, br.s), 3.39 (2H, br.s),2.92 (2H, br.s), 2.73 (2H, br.s), 2.28 (3H, br.s), 1.27 (3H, br.s).

[2781] MS (ESI) m/z: 566 [(M+H)⁺], 564 [(M−H)⁻].

Example 2722-{5-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate

[2782] Step 1. ethyl(5-amino-2-pyridinyl)acetate

[2783] To a solution of (5-amino-2-pyridinyl)acetic acid (1.46 g, 9.6mmol, Daisley; R. W.; Hanbali, J. R., Synthetic Communications., 1981,11 (9), 743.) in ethanol was added conc. H₂SO₄ and stirred for 16.5 hunder hydrogen atmosphere at room temperature. The mixture wasneutralized with saturated NaHCO₃ aqueous solution and the solvent wasremoved. The mixture was diluted with water and extracted with ethylacetate (5×20 ml). The organic layer was washed with brine, dried(MgSO₄) and concentrated to give 1.2 g of title compound as brown oil.

[2784]¹H-NMR (CDCl₃) δ: 8.04 (1H, d, J=2.8 Hz), 7.07 (1H, d, J=8.2 Hz),6.96 (1H, dd, J=2.6, 8.2 Hz), 4.71 (2H, q, J=7.1 Hz), 3.72 (2H, s), 3.66(2H, br.s), 1.25 (3H, t, J=7.1 Hz).

[2785] Step 2.Ethyl{5-[5-chloro-2-nitro-4-(trifluoromehyl)anilino]-2-pyridinyl}acetate

[2786] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from ethyl (5-amino-2-pyridinyl)acetate(step 1).

[2787]¹H-NMR (CDCl₃) δ: 9.66 (1H, s), 8.60 (2H, m), 7.71 (1H, dd, J=2.6,8.4 Hz), 7.60 (1H, d, J=8.3 Hz), 7.13 (1H, s), 4.03 (2H, s).

[2788] MS (EI) m/z: 356 (M⁺).

[2789] Step 3.ethyl{5-[2-amino-5-chloro-4-(trifluoromehyl)anilino]-2-pyridinyl}acetate

[2790] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 fromethyl{5-[5-chloro-2-nitro-4-(trifluoromehyl)anilino]-2-pyridinyl}acetate(step2).

[2791]¹H-NMR (CDCl₃) δ: 7.25 (1H, d, J=1.5 Hz), 7.21 (1H, m), 7.16 (1H,s), 7.09 (1H, s), 7.47 (1H, d, J=8.2 Hz), 5.47 (1H, s), 4.20 (2H, q,J=7.2 Hz), 3.80 (2H, s), 3.77 (2H, br.s), 1.28 (3H, t, J=7.2 Hz).

[2792] Step 4. ethyl{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridiny}acetate

[2793] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 fromethyl{5-[2-amino-5-chloro-4-(trifluoromehyl)anilino]-2-pyridinyl}acetate(step 3).

[2794]¹H-NMR (CDCl₃) δ: 8.61 (1H, d, J=2.0 Hz), 8.14 (1H, s), 7.71 (1H,dd, J=2.0, 8.2 Hz), 7.62 (1H, d, J=8.2 Hz), 7.21 (1H, s), 4.27 (1H, q,J=7.3 Hz), 4.01 (2H, s), 2.79 (2H, q, J=7.6 Hz), 1.38 (3H, t, J=7.4 Hz),1.33 (3H, t, J=7.1 Hz).

[2795] Step 5.2-{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethanol

[2796] The title compound was prepared according to the proceduredescribed in step 8 of Example 266 from ethyl{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}acetate(step 4).

[2797]¹H-NMR (CDCl₃) δ: 8.57 (1H, d, J=2.50 Hz), 8.13 (1H, s), 7.67 (1H,dd, J=2.6, 8.2 Hz), 7.49 (1H, d, J=8.2 Hz), 7.20 (1H, s), 4.15 (1H, q,J=5.6 Hz), 3.20 (2H, t, J=5.4 Hz), 2.79 (2H, q, J=7.4 Hz), 1.39 (3H, t,J=7.6 Hz).

[2798] Step 6.2-{5-[6-chloro-2-ethy-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethyll(4methylphenyl)sulfonylcarbamate

[2799] The title compound was prepared according to the proceduredescribed in Example 3 from2-{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethanol(step5).

[2800]¹H-NMR (CDCl₃) δ: 8.59 (1H, d, J=2.3 Hz), 8.13 (1H, s), 7.88 (2H,d, J=8.4 Hz), 7.65 (1H, dd, J=2.5, 8.2 Hz), 7.44 (1H, d, J=8.1 Hz), 7.32(2H, d, J=8.1 Hz), 7.20(1H, s), 4.57 (2H, t, J=6.4 Hz), 3.25 (2H, t,J=6.6 Hz), 2.79 (2H, q, J=7.4 Hz), 2.42 (3H, s), 1.38 (3H, t, J=7.4 Hz).

[2801] MS (ESI) m/z: 567 [(M+H)⁺].

Example 2732-{5-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamatehydrochloride

[2802] The title compound was prepared according to the proceduredescribed in Example 240 from2-{5-[6-chloro-2-ethy-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethyl](4methylphenyl)sulfonylcarbamate(Example 273).

[2803]¹H-NMR (DMSO-d₆) δ: 11.9 (1H, br.s), 8.72 (1H, br.s), 8.18 (1H,s), 8.03-8.07 (1H, m), 7.74 (1H, d, J=7.6 Hz), 7.58 (1H, d, J=8.2 Hz),7.43 (2H, d, J=5.1 Hz), 7.39(1H, s), 4.45 (2H, t, J=6.2 Hz), 3.17 (2H,t, J=6.2 Hz), 2.76 (2H, q, J=7.6 Hz), 2.35 (3H, s), 1.27 (3H, t, J=7.3Hz).

[2804] MS (ESI) m/z: 567 [(M+H)⁺], 565 [(M−H)⁻].

Example 2742-Ethyl-3-(4-{2-[({[4-pyridinylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2805] The title compound was prepared according to the proceduredescribed in step 2 of Example 18 from phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 18) and pyridinyl-4-sulfonamide (Chern, Ji-Wang; Leu,Yu-Ling; et al., J. Med. Chem., 1997, 40, 2276.; Graham, Samuel L.;Shepard, Kenneth L.; et al., J. Med. Chem., 1989, 32, 2548).

[2806] m.p.: 227.9-228.7° C.

[2807]¹H-NMR (CDCl₃) δ: 8.63 (2H, d, J=5.9 Hz), 7.65 (2H, d, J=5.9 Hz),7.36 (4H, s), 6.96 (1H, s), 3.20 (2H, br.s), 2.75(br.s, 2H), 2.70 (2H,q, J=7.6 Hz), 2.53 (2H, s), 2.40 (3H, s), 1.20 (3H, t, J=7.6 Hz).

[2808] MS (ESI) m/z: 479 [(M+H)⁺], 477 [(M−H)⁻].

Example 2752-Ethyl-3-(4-{2-[({[2-pyridinylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2809] The title compound was prepared according to the proceduredescribed in step 2 of Example 18 from phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 18) and pyridinyl-2-sulfonamide (Chern, Ji-Wang; Leu,Yu-Ling; et al., J. Med. Chem., 1997, 40, 2276.; Graham, Samuel L.;Shepard, Kenneth L.; et al., J. Med. Chem., 1989, 32, 2548).

[2810]¹H-NMR (CDCl₃) δ: 8.51 (1H, br.s), 8.08 (1H, br.s), 7.94 (1H,br.s), 7.29 (2H, s), 7.19 (1H, br.s), 6.91 (1H, s), 2.81 (2H, br.s),2.73 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.78 (3H, s), 2.49(m, 2H), 1.26(3H, t, J=7.3 Hz).

[2811] MS (ESI) m/z: 479 [(M+H)⁺], 477 [(M−H)⁻].

Example 2762-Ethyl-3-(4-{2-[({[3-pyridinylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

[2812] The title compound was prepared according to the proceduredescribed in step 2 of Example 18 from phenyl2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate(step 1 of Example 18) and pyridinyl-3-sulfonamide (Chern, Ji-Wang; Leu,Yu-Ling; et al., J. Med. Chem., 1997, 40, 2276.; Graham, Samuel L.;Shepard, Kenneth L.; et al., J. Med. Chem., 1989, 32, 2548).

[2813]¹H-NMR (CDCl₃) δ: 9.15 (1H, d, J=1.9 Hz), 8.83 (1H, dd, J=1.9, 5.1Hz), 8.34 (1H, dd, J=6.5 Hz), 7.50 (1H, dd, J=4.9, 8.1 Hz), 7.12-7.23(4H, m), 6.93 (1H, s), 5.92 (1H, br.s), 3.51 (2H, q, J=5.9 Hz), 2.86(2H, m), 2.69 (3H, m), 2.66 (3H, s), 2.43(3H, s), 1.27 (3H, t, J=7.6Hz).

[2814] MS (ESI) m/z: 479 [(M+H)⁺].

Example 2772-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2-phenyl}ethyl-(2-chlorophenyl)sulfonylcarbamate

[2815] The title compound was prepared according to the proceduredescribed in step 2 of Example 243 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylphenyl carbonate and 2-chlorophenylsulfonamnide.

[2816]¹H-NMR (CDCl₃) δ: 8.18 (1H, s), 8.07 (1H, d, J=7.8 Hz), 7.69 (1H,d, J=3.8 Hz), 7.59 (1H, dd, J=4.3, 8.1 Hz), 7.51 (2H, d, J=8.4 Hz), 7.44(2H, d, J=8.4 Hz), 7.31 (1H, s), 4.29 (2H, t, J=6.2 Hz), 2.94 (2H, t,J=6.5 Hz), 2.76 (2H, q, J=7.6 Hz), 1.26 (3H, t, J=7.3 Hz)

[2817] m.p. 202.4-202.8° C.

[2818] MS (ESI) m/z: 586 [(M+H)⁺], 584 [(M−H)⁻].

Example 2782-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1,1-dimethylthyl(4-methylphenyl)sulfonylcarbamate

[2819] Step 1. 2-methyl-1-(4-nitrophenyl)-2-propanol

[2820] To a solution of 1,1-dimethyl-2-(4-nitrophenyl)ethyl acetate (52mmol) in MeOH (50 ml) was added 4N-LiOH (40 ml) and the mixture wasstirred at 50° C. for 2 h. After the solvent was removed, this mixturewas diluted with water and extracted with EtOAc (4×50 ml). The organiclayer was washed with brine, dried (MgSO₄) and concentrated. This crudewas purified by SiO₂ column chromatography developing with hexane/ethylacetate (5/1) to give the title compound as yellow oil (3.3 g, 33%).

[2821]¹H-NMR (CDCl₃) δ: 8.17 (2H, d, J=8.9 Hz), 7.40 (2H, d, J=8.6 Hz),2.88 (2H, s), 1.63 (1H, br.s), 1.25 (6H, s).

[2822] Step 2. 1-(4-aminophenyl)-2-methyl-2-propanol

[2823] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-methyl-1-(4-nitrophenyl)-2-propanol (step1).

[2824]¹H-NMR (CDCl₃) δ: 7.00 (2H, d, J=8.4 Hz), 6.65 (2H, d, J=8.4 Hz),3.61 (2H, br.s), 2.65 (2H, s), 1.39 (1H, br.s), 1.20 (6H, s).

[2825] Step 3.1-{4-[(4-,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-methyl-2-propanol

[2826] The title compound was prepared according to the proceduredescribed in step 5 of Example 266 from1-(4-aminophenyl)-2-methyl-2-propanol (step2)

[2827]¹H-NMR (CDCl₃) δ: 9.60 (1H, s), 7.59 (2H, d, J=8.7 Hz), 7.19 (2H,d, J=8.4 Hz), 6.52 (1H, s), 2.75 (2H, s), 2.54 (3H, s), 2.43 (3H, s),1.24 (6H, s).

[2828] Step 4.1-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}-2-methyl-2-propanol

[2829] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from1-{4-[(-4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-methyl-2-propanol(step3)

[2830]¹H-NMR (CDCl₃) δ: 7.10 (4H, s), 6.61 (1H, s), 6.33 (2H, s), 3.28(1H, br.s), 2.70 (2H, s), 2.37 (3H, s), 2.20 (3H, s), 1.22 (6H, s).

[2831] Step 5.2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-2-methyl-2-propanol

[2832] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}-2-methyl-2-propanol(step 4).

[2833]¹H-NMR (CDCl₃) δ: 7.42 (2H, d, J=8.1 Hz), 7.33 (2H, d, J=8.47 Hz),6.91 (1H, s), 2.87 (2H, s), 2.84 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.52(3H, s), 1.31 (6H, s), 1.28 (2H, d, J=7.6 Hz).

[2834] Step 6.2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1,1-dimethylethyl(4-methylphenyl)sulfonylcarbamate

[2835] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-2-methyl-2-propanol(step 5).

[2836]¹H-NMR (CDCl₃) δ: 7.94 (2H, t, J=8.6 Hz), 7.33 (2H, d, J=8.6 Hz),7.16 (4H, m), 6.93 (1H, s), 3.10 (2H, s), 2.81 (2H, q, J=7.6 Hz), 2.67(3H, s), 2.54 (3H, s), 2.40 (3H, s), 2.42 (3H, s), 1.48 (6H, s), 1.28(3H, t, J=7.6 Hz).

[2837] m.p. 173.5-174.0° C.

[2838] MS (ESI) m/z: 521 [(M+H)⁺], 519 [(M−H)⁻].

Example 2796-Chloro-2-ethyl-1-(6-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole

[2839] Step 1.(6-{[5-chloro-2-nitro-4-(trifluoromehyl)phenyl]amino}-3-pyridinyl)methanol

[2840] The title compound was prepared according to the proceduredescribed in step 5 of Example 266 from 1-(6-amino-3-pyridinyl)methanol.

[2841]¹H-NMR (CDCl₃) δ: 10.51 (1H, br.s), 9.26 (1H, s), 8.60 (1H, s),8.42 (1H, s), 7.79 (1H, d, J=8.1 Hz), 7.01 (1H, d, J=8.1 Hz), 4.75 (2H,s).

[2842] Step 2.(6-{[2-amino-5-chloro-4-(trifluoromehyl)phenyl]amino}-3-pyridinyl}methanol

[2843] The title compound was prepared according to the proceduredescribed in step 2 of Example 28from{5-[5-chloro-2-nitro-4-(trifluoromehyl)anilino]-3-pyridinyl}methanol(step 1).

[2844] MS (EI) m/z: 317 (M⁺).

[2845] Step 3.{6-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-3-pyridinyl}methylproionate

[2846] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from(6-{[2-amino-5-chloro-4-(trifluoromehyl)phenyl]amino}-3-pyridinyl}methanol.(Step 2).

[2847] MS (EI) m/z: 411 (M⁺).

[2848] Step 4{6-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-3-pyridinyl}methanol;

[2849] The title compound was prepared according to the proceduredescribed in step 6 of Example 1from{5-[5-chloro-2-nitro-4-(trifluoromehyl)anilino]-3-pyridinyl}methylpropionate (step 3).

[2850]¹H-NMR (CDCl₃) δ: 8.67 (1H, s), 8.19 (1H, s), 8.09 (1H, d, J=8.6Hz), 7.79 (1H, d, J=8.4 Hz), 7.65 (1H, s), 5.54 (1H, t, J=5.6 Hz), 4.69(2H, d, J=5.6 Hz), 2.95 (2H, q, J=7.3 Hz), 1.27 (3H, t, J=7.2 Hz).

[2851] Step 56-chloro-1-[5-(chloromethyl)-2-pyridinyl]-2-ethyl-5-(trifluoromehyl)-1H-benzimidazole

[2852] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from{5-[5-chloro-2-nitro-4-(trifluoromehyl)anilino]-3-pyridinyl}mehtanol(step 4).

[2853]¹H-NMR (CDCl₃) δ: 8.72 (1H, d, J=2.2 Hz), 8.12 (1H, s), 8.07 (1H,dd, J=2.2, 8.1 Hz), 7.45-7.48 (2H, m), 4.72 (2H, s), 3.01 (2H, q, J=7.6Hz), 1.39 (3H, t, J=7.6 Hz).

[2854] Step 6{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-yl]-3-pyridinyl}acetonitrile

[2855] To a solution of6-chloro-1-[5-(chloromethyl)-2-pyridinyl]-2-ethyl-5-(trifluoromehyl)-1H-benzimidazole(from step 5, 550 mg, 1.5 mmol) in DMF (5 ml) and water (1 ml) was addedKCN (470 g, 7.2 mmol) at room temperature, and then the reaction mixturewas stirred for 2 h. The mixture was diluted with water and extractedwith ethyl acetate/toluene (4/1) solution (3×30 ml). The organic layerwas washed with water, dried (MgSO₄) and concentrated. This was purifiedby SiO₂ column chromatography developing with hexane/ethyl acetate (1/)gave 198 mg (37%) of title compound as orange oil.

[2856]¹H-NMR (CDCl₃) δ: 8.70 (1H, d, J=2.6 Hz), 8.13 (1H, s), 8.06 (1H,dd, J=2.6, 8.0 Hz), 7.52 (1H, d, J=8.20 Hz), 7.47 (1H, s), 3.94 (2H, s),3.01 (2H, q, J=7.5 Hz), 1.40 (3H, t, J=7.5 Hz).

[2857] Step 72-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-yl]-3-pyridinyl}ethanamine

[2858] The title compound was prepared according to the proceduredescribed in step 5 of Example 270from{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-yl]-3-pyridinyl}acetonitrile(step 6).

[2859] MS (EI) m/z: 368 (M⁺).

[2860] Step 86-chloro-2-ethyl-1-(6-{2-[({[(4methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-2-pyridinyl)-5-(trifluoromehyl)-1H-benzimidazol

[2861] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethanamine(step 7).

[2862]¹H-NMR (CDCl₃) δ: 8.50 (1H, s), 8.12 (1H, s), 7.817 (1H, d, J=6.0Hz), 7.72 (2H, d, J=8.4 Hz), 7.42 (1H, s), 7.24-7.37 (3H, m), 7.21 (1H,s), 6.77 1, br.s), 3.60 (2H, dt, J=6.2 Hz), 2.94-3.01 (4H, m), 2.37 (3H,s), 1.37 (3H, t, J=7.5 Hz).

[2863] MS (ESI) m/z: 566 [(M+H)⁺], 564 [(M−H)⁻].

Example 2802-{4-[5-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1,1-dimethylethyl(4-methylphenyl)sulfonylcarbamate

[2864] Step 1.1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-methyl-2-propanol

[2865] The title compound was prepared according to the proceduredescribed in step 5 of Example 266 from1-(4-aminophenyl)-2-methyl-2-propanol

[2866]¹H-NMR (CDCl₃) δ: 9.70 (1H, br.s), 8.58 (1H, s), 7.36 (2H, d,J=8.4 Hz), 7.21-7.25 (3H, m), 2.83 (2H, s), 1.28 (6H, s).

[2867] MS (EI) m/z: 388 (M⁺).

[2868] Step 2.1-(4-{[2-amino-5-chrolo-4-(trifluoromethyl)phenyl]amino}phenyl)-2-methyl-2-propanol

[2869] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-methyl-2-propanol(step 1)

[2870]¹H-NMR (CDCl₃) δ: 7.10 (4H, s), 6.61 (1H, s), 6.33 (2H, s), 3.28(1H, br.s), 2.70 (2H, s), 2.37 (3H, s), 2.20 (3H, s), 1.22 (6H, s).

[2871] MS (EI) 388 (M⁺).

[2872] Step 3.1-{4-[6-chrolo-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-methyl-2-propanol

[2873] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-(4-{[2-amino-5-chrolo-4-(trifluoromethyl)phenyl]amino}phenyl)-2-methyl-2-propanol(step 2).

[2874]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.48 (2H, d, J=8.4 Hz), 7.28 (2H,d, J=8.4 Hz), 7.22 (1H, s), 2.90 (2H, s), 2.80 (2H, q, J=7.3 Hz), 1.36(3H, t, J=7.3 Hz) 1.32 (6H, s).

[2875] MS (EI) m/z: 396 (M⁺).

[2876] Step 4.2-{4-[5-chrolo-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1,1-dimethylethyl(4-methylphenyl)sulfonylcarbamate

[2877] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-2-methyl-2-propanol(step 3).

[2878]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.94 (2H, d, J=8.7 Hz), 7.36 (2H,d, J=8.1 Hz), 7.15-7.27 (5H, m), 3.16 (2H, s), 2.78 (2H, q, J=7.6 Hz),2.43 (3H, s), 1.47 (6H, s), 1.37 (3H, t, J=7.6 Hz)

[2879] m.p. 174.6-175.3° C.

[2880] MS (ESI) m/z: 594 [(M+H)⁺], 592 [(M−H)⁻].

Example 2812-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(2,4-dimethyl-1,3-thiazol-5-yl)sulfonylcarbamate

[2881] The title compound was prepared according to the proceduredescribed in step 2 of Example 243 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylphenyl carbonate and 2,4-dimethyl-1,3-thiazol-5-yLsulfonamide.

[2882]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.41 (2H, d, J=7.9 Hz), 7.27 (2H,d, J=7.9 Hz), 7.20 (1H, s), 4.45 (2H, t, J=6.9 Hz), 3.08 (2H, t, J=6.6Hz), 2.79 (2H, q, J=7.7 Hz), 2.71 (3H, s), 2.68 (3H, s), 1.36 (3H, t,J=7.7 Hz).

[2883] m.p. 168.3-169.0° C.

[2884] MS (ESI) m/z: 587 [(M+H)⁺], 585 [(M−H)⁻].

Example 2822-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonylcarbamate

[2885] The title compound was prepared according to the proceduredescribed in step 2 of Example 243 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylphenyl carbonate and 5-chloro-1,3-dimethyl-1H-pyrazol4-yl sulfonamide.

[2886]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.41 (2H, d, J=7.9 Hz), 7.27 (2H,d, J=7.9 Hz), 7.20 (1H, s), 4.45 (2H, t, J=6.9 Hz), 3.08 (2H, t, J=6.6Hz), 2.79 (2H, q, J=7.7 Hz), 2.71 (3H, s), 2.68 (3H, s), 1.36 (3H, t,J=7.7 Hz)

[2887] m.p. 192.0-192.7° C.

[2888] MS (ESI) m/z: 604 [(M+H)⁺], 602 [(M−H)⁻].

Example 2832-{4-[5-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}propyl(4-methylphenyl)sulfonylcarbamate

[2889] Step 1. 2-(4-aminophenyl)1-propanol

[2890] To a stirred solution of 2-(4-amino-phenyl)-propionic acid ethylester (5.0 g, 25.9 mmol, Takahashi, I. et al., Heterocycles 1996, 43,2343-2346.) in tetrahydrofurane (200 ml) was slowly addedlithiumaluminium hydride (1.96 g, 51.8 mmol), and the mixture wasstirred at room temperature for 14 h. The reaction mixture was quenchedwith 25% ammonia solution (SOml) under ice-bath cooling. The resultingprecipitate was filtered off, and the filtrate concentrated underreduced pressure to afford 3.88 g (99%) of the title compound as slightbrown syrup.

[2891]¹H-NMR (CDCl₃) δ: 7.03 (2H, d, J=8.5 Hz), 6.66 (2H, d, J=8.5 Hz),3.70-3.57 (4H, m), 2.90-2.78 (1H, m), 1.34-1.30 (1H, m), 1.22 (3H, d,J=7.1 Hz).

[2892] MS (EI) m/z: 151 (M⁺).

[2893] Step 2. 2-(4-{[5-chrolo-2-nitro-4-(trifluoromethyl)phenyl]aminophenyl)-1-propanol

[2894] The title compound was prepared according to the proceduredescribed in step 5 of Example 266 from 2-(4-aminophenyl)1-propanol(step 1)

[2895]¹H-NMR (CDCl₃) δ: 9.69 (1H, br.s), 8.58 (1H, s), 7.38 (2H, d,J=8.3 Hz), 7.21-7.26 (3H, m), 3.77 (2H, m), 3.03 (1H, m), 1.41 (1H, t,J=5.7 Hz), 1.33 (3H, d, J=7.1 Hz).

[2896] Step 3.2-(4-{[2-amino-5-chrolo-4-(trifluoromethyl)phenyl]amino}phenyl)-1-propanol

[2897] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-(4-{[5-chrolo-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-1-propanol(step2)

[2898]¹H-NMR (CDCl₃) δ: 7.21-7.26 (3H, m), 7.07 (1H, s), 6.93 (2H, d,J=8.4 Hz), 5.41 (1H, br.s), 3.68-3.69 (2H, br.s), 2.93 (1H, m), 1.38(1H, br.s), 1.28 (3H, d, J=7.1 Hz).

[2899] Step 4.2-{4-[6-chrolo-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-propanol

[2900] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-(4-{[2-amino-5-chrolo-4-(trifluoromethyl)phenyl]amino}phenyl)1-propanol(step 3).

[2901]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.49 (2H, d, J=2.3 Hz), 7.30 (2H,d, J=8.4 Hz), 7.22 (1H, s), 3.83 (2H, m), 3.11 (1H, m), 2.80 (2H, q,J=7.6 Hz) 1.57 (1H, m), 1.33-1.40 (6H, m).

[2902] Step 5.2-{4-[5-chrolo-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1,1-dimethylethyl(4-methylphenyl)sulfonylcarbamate

[2903] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-propanol(step 4).

[2904]¹H-NMR (CDCl₃) δ: 8.11 (1H, s), 7.904 (2H, d, J=8.4 Hz), 7.40 (2H,d, J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz), 7.27 (1H, s), 7.24 (1H, s), 7.20(1H, s), 4.19-4.30 (2H, m), 3.20 (1H, m), 2.78 (2H, q, J=7.5 Hz), 2.43(3H, s), 1.53 (3H, t, J=7.56 Hz), 1.34 (3H, t, J=6.9 Hz).

[2905] m.p. 179.9-180.5° C.

[2906] MS (ESI) m/z: 581 [(M+H)⁺], 579 [(M−H)⁻].

Example 2842-[4-(5-Acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1,1-dimethylethyl(4-methylphenyl)sulfonylcarbamate

[2907] Step 1.1-(4-{[4-hydroxy-2-methylpropyl)phenyl]amino}-3-nitrophenyl)ethanone

[2908] The title compound was prepared according to the proceduredescribed in step 5 of Example 266 from1-(4-aminophenyl)-2-methyl-2-propanol

[2909]¹H-NMR (CDCl₃) δ: 9.85 (1H, br.s), 8.83 (1H, s), 7.97 (1H, d,J=9.0 Hz), 7.10-7.40 (4H, m), 2.82 (2H, s), 2.58 (3H, s), 1.28 (6H, s).

[2910] Step 2.1-(3-amino-4-{[4-(2-hydroxy-2-methylpropyl)phenyl]amino}phenyl)ethanone

[2911] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from1-(4-{[4-hydroxy-2-methylpropyl)phenyl]amino}-3-nitrophenyl)ethanone(step 1).

[2912]¹H-NMR (CDCl₃) δ: 7.38-7.46 (2H, m), 7.16 (2H, dd, J=8.4 Hz), 6.96(2H, d, J=8.4 Hz), 5.62 (2H, br.s), 3.60 (1H, br.s), 2.73 (2H, s), 2.54(3H, s), 1.39 (1H, br.s), 1.24 (6H, s).

[2913] Step 3. 1-12-ethyl-1-[4-(2-hydroxy-2-methylpropyl)phenyl]-1H-benzimidazol-5-yl}ethanone

[2914] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-(3-amino-4-{[4-(2-hydroxy-2-methylpropyl)phenyl]amino}phenyl)ethanone(step 2).

[2915]¹H-NMR (CDCl₃) δ: 8.40 (1H, s), 7.90 (1H, d, J=8.6 Hz), 7.46 (2H,d, J=8.1 Hz), 7.30 (2H, d, J=8.1 Hz), 7.14 (1H, d, J=8.6 Hz), 2.96 (2H,s), 2.82 (2H, q, J=7.6 Hz), 2.68 (3H, s), 1.63 (1H, br.s), 1.38 (3H, t,J=7.6 Hz), 1.32 (6H, s).

[2916] Step 4.2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1,1-dimethylethyl(4-methylphenyl)sulfonylcarbamate

[2917] The title compound was prepared according to the proceduredescribed in Example 3 from1-{2-ethyl-1-[4-(2-hydroxy-2-methylpropyl)phenyl]-1H-benzimidazol-5-yl}ethanone(step 3).

[2918]¹H-NMR (CDCl₃) δ: 8.41 (1H, s), 7.88-7.95 (3H, m), 7.09-7.35 (7H,m), 3.14 (2H, s), 2.80 (2H, q, J=7.6 Hz), 2.68 (3H, s), 2.40 (3H, s),1.45 (6H, s), 1.38 (3H, t, J=7.6 Hz).

[2919] m.p. 103.4-104.2° C.

[2920] MS (ESI) m/z: 534 [(M+H)⁺], 532 [(M−H)⁻].

Example 2852-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-methyl-2-pyridinyl)sulfonylcarbamatemono-hydrochloride

[2921] The title compound was prepared according to the proceduredescribed in step 2 of Example 243 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylphenyl carbonate.

[2922]¹H-NMR (CDCl₃) δ: 8.57 (1H, s), 8.15 (1H, s), 8.12 (1H, d, J=8.0Hz), 7.77 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=7.9 Hz), 7.17-7.25 (4H, m,),4.36 (2H, t, J=6.6 Hz), 3.00 (2H, t, J=6.6 Hz), 2.77 (2H, q, J=7.5 Hz),2.46 (3H, s), 1.36 (3H, t, J=7.3 Hz).

[2923] m.p. 205.8 ° C.

[2924] MS (ESI) m/z: 567 [(M+H)⁺], 565 [(M−H)⁻].

Example 2862-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-methyl-2-pyridinyl)sulfonylcarbamatemono-hydrochloride mono-hydrochloride

[2925] The title compound was prepared according to the proceduredescribed Example 240 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-methyl-2-pyridinyL)sulfonylcarbamate(Example 285).

[2926]¹H-NMR (CDCl₃) δ: 8.53 (1H, s), 8.49 (1H, s), 8.08 (1H, d, J=7.6Hz), 7.78 (1H, d, J=6.8 Hz), 7.53 (2H, br.s), 7.41 (3H, br.s), 4.38 (2H,t, J=5.9 Hz), 3.21 (2H, br.s), 3.07 (2H, t, J=5.9 Hz), 2.47 (3H, s),1.51 (3H, br.s).

[2927] m.p. 200.2° C.

[2928] MS (ESI) m/z: 567 [(M+H)⁺], 565 [(M−H)⁻].

Example 2872-{5-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate

[2929] Step 1. benzyl ethyl 2-(6-nitro-3-pyridinyl)malonate

[2930] To a mixture of 5-bromo-2-nitropyridine (8.66 g, 42.7 mmol) andbenzyl ethyl malonate (9.50 g, 42.7 mmol) in tetrahydrofuran (160 ml)and dimethylformamide (40 ml) was added K₂CO₃ (5.90 g, 42.7 mmol) andstirred under reflux temperature for 20 h. The mixture was diluted withwater (1 l) and extracted with ethyl acetate (3×200 ml). The organiclayer was washed with brine, dried (MgSO₄) and concentrated to give 5.26g of title compound as orange oil.

[2931]¹H-NMR (CDCl₃) δ: 8.61 (1H, d, J=2.2 Hz), 8.26 (1H, d, J=8.4 Hz),8.19 (1H, dd, J=2.1, 8.6 Hz), 7.29-7.38 (5H, m), 5.22 (2H, d, J=3.6 Hz),4.84 (1H, s), 4.22 (2H, m), 1.23 (3H, t, J=7.1 Hz).

[2932] Step 2. ethyl (6-nitro-3-pyridinyl)acetate

[2933] To a solution of benzyl ethyl 2-(6-nitro-3-pyridinyl)malonate(5.26 g, 15.3 mmol,) in ethanol was added palladium on carbon (530 mg)and stirred for 6 h under hydrogen atmosphere at room temperature. Thecatalyst was filtered off through a pad of celite and the filtrate wasconcentrated to give a title compound as yellow brown oil.

[2934]¹H-NMR (CDCl₃) δ: 7.95 (1H, d, J=1.8 Hz), 7.40 (1H, dd, J=2.4, 8.4Hz), 6.48 (1H, d, J=8.4 Hz), 4.42 (2H, br.s), 4.14 (2H, q, J=7.1 Hz),3.46 (2H, s), 1.26 (3H, t, J=7.1 Hz).

[2935] Step 3. 2-(6-amino-3-pyridinyl)ethanol

[2936] To a solution of ethyl (6-nitro-3-pyridinyl)acetate (468 mg, 2.60mmol) in tetrahydrofuran was added LiAlH₄ and stirred for 2 h at roomtemperature. The reaction was quenched with saturated 25% NH₃ aqueoussolution and the precipitate was removed. The filtrate was concentratedto give a title compound as yellow oil.

[2937]¹H-NMR (CDCl₃) δ: 7.73 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=8.6 Hz),6.37 (1H, d, J=2.6, 8.1 Hz), 5.63 (2H, br.s), 3.49 (2H, t, J=7.3 Hz),2.51 (2H, t, J=7.3 Hz).

[2938] MS (EI) m/z: 138 (M⁺).

[2939] Step 4.(6-{[5-chloro-2-nitro-4-(trifluoromehyl)phenyl]amino}-3-pyriydinyl}ethanol

[2940] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 2-(6-amino-3-pyridinyl)ethanol(step 3).

[2941]¹H-NMR (CDCl₃) δ: 8.49 (1H, s), 8.32 (1H, d, J=2.2 Hz), 7.64 (1H,dd, J=2.4, 8.4 Hz), 7.36 (1Hs), 6.97 (1H, d, J=8.4 Hz), 3.91 (2H, t,J=6.5 Hz), 2.89 (2H, t, J=6.5 Hz).

[2942] MS (EI) m/z: 361 (M⁺).

[2943] Step 5.(6-{[2-amino-5-chloro-4-(trifluoromehyl)phenyl]amino}-3-pyridinyl}ethanol

[2944] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from(6-{[5-chloro-2-nitro-4-(trifluoromehyl)phenyl]amino}-3-pyridinyl}ethanol(step 4).

[2945] MS (EI) m/z: 331 (M⁺).

[2946] Step 6.2-{6-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethylpropionate

[2947] To(6-{[2-amino-5-chloro-4-(trifluoromehyl)phenyl]amino}-3-pyridinyl}ethanol(787 mg, 2.37 mmol, from step 5) was added propionic acid and propionicanhydride and stirred at 120° C. for 15 h. The mixture was quenched withNaOH and extracted with dichloromethane (3×30 ml). The organic layer waswashed with brine, dried (MgSO₄) and concentrated to give 5.26 g oftitle compound as orange oil.

[2948]¹H-NMR (CDCl₃) δ: 8.58 (1H, d, J=1.9 Hz), 8.12 (1H, s), 7.83 (1H,dd, J=2.2, 8.1 Hz), 7.45 (1H, s), 7.39 (1H, d, J=8.1 Hz), 4.40 (2H, t,J=6.8 Hz), 4.12 (2H, q, J=7.3 Hz), 3.10 (2H, t, J=6.5 Hz), 2.99 (2H, q,J=7.6 Hz), 2.29-2.44 (2H, m), 1.38 (3H, t, J=7.4 Hz), 1.15 (3H, t, J=7.6Hz).

[2949] Step 5.2-{6-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-3-piridinyl}ethanol

[2950] The title compound was prepared according to the proceduredescribed in step 8 of Example 266 from2-{6-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethylpropionate(step 4).

[2951]¹H-NMR (CDCl₃) δ: 8.60 (1H, d, J=2.3 Hz), 8.11 (1H, s), 7.91 (1H,dd, J=2.5, 8.0 Hz), 7.45 (1H, s), 7.38 (1H, d, J=8.1 Hz), 4.01 (1H, t,J=6.2 Hz), 3.72-3.77 (2H, m), 2.94-3.04 (2H, m), 1.38 (3H, t, J=7.4 Hz).

[2952] Step 6.2-{6-[6-chloro-2-ethy-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethyl-(4-methylphenyl)sulfonylcarbamate

[2953] The title compound was prepared according to the proceduredescribed in Example 3 from2-{6-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethanol(step 5).

[2954]¹H-NMR (CDCl₃) δ: 8.33 (1H, d, J=1.9 Hz), 8.08 (1H, s), 7.91 (2H,d, J=8.4 Hz), 7.70 (1H, dd, J=2.4, 8.1 Hz), 7.29-7.42 (4H, m), 7.20(1H,s), 4.39 (2H, t, J=6.2 Hz), 3.00 (2H, t, J=6.2 Hz), 2.93 (2H, t, J=7.6Hz), 2.43 (3H, s), 1.32 (3H, t, J=7.4 Hz).

[2955] MS (ESI) m/z: 567 [(M+H)⁺], 565 [(M−H)⁻].

Example 2882-{5-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamatemono-hydrochloride

[2956] Step 1.

[2957] The title compound was prepared according to the proceduredescribed in Example 240 from2-{5-[6-chloro-2-ethy-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethyll-(4-methylphenyl)sulfonylcarbamate(Example 287).

[2958]¹H-NMR (CDCl₃) δ: 8.40 (1H, br.s), 8.49 (1H, br.s), 8.12 (1H,br.s), 7.82 (2H, br.s), 7.65 (1H, br.s), 7.25-7.28 (2H, m), 4.40 (2H,br.s), 3.35 (1H, s), 3.12 (2H, br.s), 2.41 (3H, s), 2.43 (3H, s), 1.53(3H, br.s).

[2959] MS (ESI) m/z: 567 [(M+H)⁺], 565 [(M−H)⁻].

Example 2892-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-5-isoquinolinylsulfonylcarbamate

[2960] The title compound was prepared according to the proceduredescribed in step 2 of Example 243 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylphenyl carbonate and 5-isoquinolinylsulfonamide.

[2961]¹H-NMR (CDCl₃) δ: 9.39 (1H, s), 8.70 (2H, t, J=6.3 Hz), 8.43 (1H,d, J=6.2 Hz), 8.29 (1H, d, J=8.1 Hz), 8.12 (1H, s,), 7.78 (1H, t, J=7.6Hz), 7.16-7.33 (5H, m), 4.32 (2H, t, J=6.9 Hz), 2.97 (2H, t, J=6.8 Hz),2.77 (2H, q, J=7.4 Hz), 1.346 (3H, t, J=7.4 Hz).

[2962] MS (ESI) m/z: 603 [(M+H)⁺], 601 [(M−H)⁻].

Example 2902-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-5-quinolinylsulfonylcarbamate

[2963] The title compound was prepared according to the proceduredescribed in step 2 of Example 243 from4-(6-chloro-2-ethyl-5-trifluoromethyl-1-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamateand 5-quinolinylsufonamide

[2964]¹H-NMR (CDCl₃) δ: 8.43 (1H, d, J=8.6 Hz), 8.20-8.25 (2H, m), 8.13(1H, s), 8.12 (1H, s,), 7.81-7.91 (2H, m), 7.68-7.72 (1H, m), 7.30-7.34(2H, m), 7.12-7.16 (3H, m), 4.37 (2H, t, J=6.6 Hz), 2.98 (2H, t, J=6.3Hz), 2.74 (2H, q, J=7.4 Hz), 1.35 (3H, t, J=7.4 Hz).

[2965] MS (ESI) m/z: 567 [(M+H)⁺], 565 [(M−H)⁻].

Example 2912-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-[5-(dimethylamino)-1-naphthnyl]sulfonylcarbamate

[2966] The title compound was prepared according to the proceduredescribed in step 2 of Example 243 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylphenyl carbonate and 5-(dimethylamino)-1-naphthnylsulfonamide.

[2967]¹H-NMR (CDCl₃) δ: 8.61 (1H, d, J=8.4 Hz), 8.46 (1H, dd, J=1.2, 7.5Hz), 8.12 (1H, s), 87.58 (2H, t, J=8.3 Hz), 7.12-7.24 (6H, m), 4.30 (2H,t, J=6.8 Hz), 2.93 (2H, t, J=6.8 Hz), 2.75 (2H, q, J=7.5 Hz), 1.35 (3H,t, J=7.5 Hz).

[2968] m.p. 203.4° C.

[2969] MS (ESI) m/z: 645 [(M+H)⁺], 643 [(M−H)⁻].

Example 2922-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(1-methyl-1H-imidazol-4-yl)sulfonylcarbamate

[2970] The title compound was prepared according to the proceduredescribed in step 2 of Example 243 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylphenyl carbonate and 1-methyl-1H-imidazol-4-ylsulfonamide.

[2971]¹H-NMR (CDCl₃) δ: 8.13 (1H, s), 7.72 (1H, d, J=1.5 Hz), 7.55 (1H,d, J=1.3 Hz), 7.41 (2H, d, J=8.2 Hz), 7.26 (2H, d, J=8.2 Hz), 7.20 (1H,s), 4.38 (2H, t, J=6.6 Hz), 3.78 (3H, s), 3.04 (2H, d, J=6.8 Hz), 2.79(2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).

[2972] m.p. 204.3° C.

[2973] MS (ESI) m/z: 556 [(M+H)⁺], 554 [(M−H)⁻].

Example 2932-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(1-methyl-1H-imidazol-4-yl)sulfonylcarbamatemono hydrochloride

[2974] The title compound was prepared according to the proceduredescribed in Example 240 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(1-methyl-1H-imidazol-4-yl)sulfonylcarbamate(Example 292).

[2975] MS (ESI) m/z: 556 [(M+H)⁺], 554 [(M−H)⁻].

Example 2942-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(1,2-dimethyl-1H-imidazol-4-yl)sulfonylcarbamate

[2976] The title compound was prepared according to the proceduredescribed in step 2 of Example 243 from2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylphenyl carbonate and 1,2-dimethyl-1H-imidazol-4-ylsulfonamide.

[2977]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.63 (1H, s), 7.41 (2H, d, J=8.2Hz), 7.25 (2H, d, J=8.2 Hz), 7.19 (1H, s), 4.37 (2H, t, J=6.8 Hz), 3.64(3H, s), 3.04 (2H, d, J=6.6 Hz), 2.79 (2H, q, J=7.6 Hz), 2.42 (3H, s),1.36 (3H, t, J=7.6 Hz).

[2978] m.p. 221.2° C.

[2979] MS (ESI) m/z: 570 [(M+H)⁺], 568 [(M−H)⁻].

Example 2952-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(1,2-dimethyl-1H-imidazol-4-yl)sulfonylcarbamatedi-hydrochloride

[2980] The title compound was prepared according to the proceduredescribed in Example 240 from2-{4-[6-chrolo-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(1,2-dimethyl-1H-imidazol-4-yl)sulfonylcarbamate(Example 294).

[2981] MS (ESI) m/z: 570 [(M+H)⁺], 568 [(M−H)⁻].

Example 2962-{4-[5,7-Dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl-]phenyl}ethyl(4-methylphenyl)sufonylcarbamate

[2982] Step 1.2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethanol

[2983] The title compound was prepared according to the proceduredescribed in step 1 of Example 236 from4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenylethanol.

[2984]¹H-NMR (DMSO-d₆) δ: 13.15 (1H, br.s), 7.77 (3H, s), 7.35 (2H, d,J=7.7 Hz), 7.25 (2H, d, J=7.7 Hz), 7.02 (1H, s), 6.53 (1H, s), 4.75 (2H,t, J=4.8 Hz), 3.71 (2H, q, J=6.8 Hz), 2.81 (1H, t, J=6.6 Hz), 258 (3H,s), 2.42 (3H, s).

[2985] Step 2. 2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)3H-imidazo[4,5-b]pyridine-3-yl-]phenyl}ethyl(4-methylphenyl)sufonylcarbamate

[2986] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethanol(step 1).

[2987]¹H-NMR (DMSO-d₆) δ: 13.14 (1H, br.s), 7.69-7.78 (3H, m), 7.21-7.43(6H, m), 7.02 (1H, s), 6.52 (1H, s), 4.18 (2H, t, J=6.4 Hz), 2.89 (2H,t, J=6.4 Hz), 2.58 (2H, s), 2.41(3H, s), 2.32 (3H, s).

[2988] MS (ESI) m/z: 531 (MH⁺), 529 ([M−H]⁻).

Example 297 2-{4-[5,7-Dimethyl-2-(1H-pyrazol-3-yl)3H-imidazo[4,5-b]pyridine-3-yl-]phenyl}ethyl(4-methylphenyl)sufonylcarbamatesodium salt

[2989] Step 1.2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethanol

[2990] The title compound was prepared according to the proceduredescribed in Example 2 from 2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)3H-imidazo[4,5-b]pyridine-3-yl-]phenyl}ethyl(4-methylphenyl)sufonylcarbamate(Example 296).

[2991]¹H-NMR (CDCl₃) δ: 9.85 (1H, s), 8.37 (1H, d, J=8.4 Hz), 7.31 (1H,d, J=2.0 Hz), 7.14 (1H, dd, J=2.0, 8.3 Hz), 6.60 (1H, s), 3.87 (2H, dt,J=6.2, 6.4 Hz), 2.84 (2H, t, J=6.4 Hz), 2.56 (3H, s), 2.46 (3H, s), 1.40(1H, t, J=6.2 Hz).

[2992] MS (ESI) m/z: 531 (MH⁺), 529 ([M−H]⁻).

Example 298N-{[(2-{4-[5,7-Dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[2993] Step 1.3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine

[2994] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethanol(Example 297, step 1).

[2995]¹H-NMR (CDCl₃) δ: 13.15 (1H, s), 7.77 (2H, br.s), 7.43 (2H, br.s),7.20 (2H, br.s), 7.04 (1H, s), 6.54 (1H, br.s), 3.96 (2H, t, J=6.8 Hz),3.15 (2H, tm J=6.8 Hz), 2.60 (3H, s), 2.30 (3H, s).

[2996] Step 2.3-[4-(2-azidoethyl)phenyl]-5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine

[2997] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine(step 1).

[2998]¹H-NMR (DMSO-d₆) δ: 13.15 (1H, br.s), 9.85 (1H, br.s), 7.76 (1H,br.s), 7.41 (2H, d, J=8.1 Hz), 7.31(2H, d, J=8.1 Hz), 7.04 (1H, s), 6.53(1H, s), 3.69 (2H, t, J=6.6 Hz), 2.95 (2H, t, J=6.8 Hz), 2.58 (3H, s),2.42 (3H, s).

[2999] MS (EI) m/z: 358 (M⁺).

[3000] Step 3.2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethanamine

[3001] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from3-[4-(2-azidoethyl)phenyl]-5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine(step 2).

[3002]¹H-NMR (DMSO-d₆) δ: 9.83 (1H, br.s), 7.68 (2H, br.s), 7.23-7.43(5H, m), 7.04 (1H, s), 5.75 (1H, s), 2.68-2.90 (4H, m), 2.59 (3H, s),2.42 (3H, s).

[3003] MS (EI) m/z: 332 (M⁺).

[3004] Step 4.N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3005] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethanamine(step3)

[3006]¹H-NMR (CD3OD) δ: 7.80 (2H, d, J=8.2 Hz), 7.58 (1H, br.s),7.20-7.35 (6H, m), 7.08 (1H, s), 6.20 (1H, br.s), 3.42 (2H, t, J=6.8Hz), 2.84 (2H, t, J=6.9 Hz), 2.68 (2H, s), 2.50 (3H, s), 2.34 (3H, s).

[3007] MS (ESI) m/z: 530 (MH⁺), 528 ([M−H]⁻).

Example 2992-[4-(5-Cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3008] Step 1. 4-Chloro-2-methyl-5-nitrobenzonitrile

[3009] To a solution of 4-chloro-2-methylbenzonitrile (10 g, 66 mmol) inconc. H₂SO₄ was added KNO₃ (7.0 g, 69.3 mmol) at 0° C. in smallportions, and then the reaction mixture was stirred overnight at ambienttemperature. It was then poured into ice and extracted with AcOEt. Thecombined extracts were washed by sat. NaHCO₃ aq., dried over MgSO₄ andconcentrated. The resulting precipitates were collected by filtration,washed with ether, and dried under reduced pressure to give 5.5 g (42%)of the title compound.

[3010]¹H-NMR (CDCl₃) δ: 8.19 (1H, s), 7.57 (1H, s), 2.64 (3H, s).

[3011] Step 2.4-{[4-(2-hydroxylethyl)phenyl]amino}-2-methyl-5-nitrobenzonitrile

[3012] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from4-chloro-2-methyl-5-nitrobenzonitrile (step 1).

[3013]¹H-NMR (CDCl₃) δ: 9.76 (1H, br.s), 8.51 (1H, s), 7.36 (1H, d,J=8.4 Hz), 7.22 (1H, d, J=8.3 Hz), 6.96 (1H, s), 3.94 (2H, dd, J=11.7,6.2 Hz), 2.94 (2H, t, J=6.4 Hz), 2.42 (3H, s)

[3014] Step 3.5-amino-4-{[4-(2-hydroxylethyl)phenyl]aminol-2-methylbenzonitrile

[3015] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from4-[4-(2-hydroxylethyl)phenyl]-2-methyl-5-nitrobenzonitrile (step 2).

[3016]¹H-NMR (CDCl₃) δ: 7.19 (1 h, d, J=8.4 Hz), 6.94-7.00 (4H, m), 5.59(1H, br.s), 3.84-3.90 (2H, m), 3.50 (2H, br.s), 2.85 (2H, t, J=6.4 Hz),2.37 (3H, s).

[3017] Step 4.2-[4-(5-cyano-2-ethyl-6-methyl-1H-benzimidazo-1-yl)phenyl]ethylpropanoate

[3018] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from5-amino-4-{[4-(2-hydroxylethel)phenyl]amino}-2methlbenzonitrile (step3).

[3019] MS (EI) m/z: 361 (M+).

[3020] Step 5.2-ethyl-1-[4-(2-hydroxylethyl)phenyl]-6-methyl-1H-benzimidazole-5-carbonitrile

[3021] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5-cyano-2-ethyl-6-methyl-1H-benzimidazo-1-yl)phenyl]ethylpropanoate(step 4).

[3022]¹H-NMR (CDCl₃) δ: 8.00 (1H, s), 7.50 (2H, d, J=8.4 Hz), 7.29 (2H,d, J=8.4 Hz), 6.98(1H, s), 4.01 (2H, t, J=6.4 Hz), 3.03 (2H, t, J=6.6Hz), 2.79 (2H, q, J=7.5 Hz), 2.56 (3H, s), 1.35 (3H, t, J=7.5 Hz).

[3023] Step 6.2-[4-(5-cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3024] The title compound was prepared according to the proceduredescribed in Example 3 from2-ethyl-1-[4-(2-hydroxylethyl)phenyl]-6-methyl-1H-benzimidazole-5-carbonitrile(step 5).

[3025]¹H-NMR (CDCl₃) δ: 8.03 (1H, s), 7.92 (2H, d, J=8.4 Hz), 7.39 (2H,d, J=8.4 Hz), 7.35 (2H, d, J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz), 6.96(1H,s), 4.39 (2H, t, J=6.8 Hz), 3.04 (2H, t, J=6.6 Hz), 2.77 (2H, q, J=7.7Hz), 2.57 (3H, s), 2.44 (3H, s), 1.35 (3H, t, J=7.5 Hz)

Example 300N-[({2-[4-(5-Cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl](4-methylbenzenesulfoamide

[3026] Step 1.1-[4-(2-chloroethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazole-5-carbonitrile

[3027] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(6-bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol(step 6).

[3028]¹H-NMR (CDCl₃) δ: 8.02 (1H, s), 7.48 (2H, d, J=8.4 Hz), 7.30 (2H,d, J=8.4 Hz), 6.96-6.98 (1H, m), 3.83 (2H, t, J=7.1 Hz), 3.21 (2H, t,J=7.0 Hz), 2.78 (2H, q, J=7.5 Hz), 2.58 (3H, s), 1.35 (3H, t, J=7.5 Hz).

[3029] Step 2.1-[4-(2-azidoethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazole-5-carbonitrile

[3030] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from6-bromo-3-[4-(2-chloroethyl)phenyl]-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(step 7).

[3031] MS (EI) m/z: 412 (M+).

[3032]¹H-NMR (CDCl₃) δ: 8.02 (1H, s), 7.48 (2H, d, J=8.0 Hz), 7.30 (2H,d, J=8.2 Hz), 6.95 (1H, s), 3.63 (2H, t, J=6.8 Hz), 3.03 (2H, t, J=7.0Hz), 2.78 (2H, q, J=7.5 Hz), 2.57 (3H, s), 1.35 (3H, t, J=7.3 Hz).

[3033] Step 3.1-[4-(2-aminoethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazole-5-carbonitrile

[3034] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from2-[4-(6-bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylazide (step 8).

[3035]¹H-NMR (CDCl₃) δ: 7.49 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz),6.93 (1H, s), 6.60 (2H, br.s), 3.32-3.00 (5H, m), 2.65 (3H, s), 2.48(3H, s), 1.31 (6H, d, J=6.8 Hz).

[3036] Step 4.N-[({2-[4-(5-cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl](4-methylbenzenesulfoamide

[3037] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from[4-(2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine(step 9).

[3038]¹H-NMR (CDCl₃) δ: 8.00 (1H, s), 7.72 (2H, d, J=8.4 Hz), 7.42 (2H,d, J=8.4 Hz), 7.28-7.32 (4H, m), 6.95(1H, m), 3.56-3.63 (2H, m), 2.96(2H, t, J=7.1 Hz), 2.78 (2H, q, J=7.7 Hz), 2.54 (3H, s), 2.41 (3H, s),1.34 (3H, t, J=7.5 Hz).

Example 3012-Amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridinedi-hydrochloride

[3039] Step 1.2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[3040] To a stirred solution ofN-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(300 mg, 0.66 mmol) in THF (6 ml) was added a solution of BrCN (175 mg,1.65 mmol) in water (2 ml). The resultant mixture was stirred at roomtemperature for 16 hours. The mixture was diluted with CH₂Cl₂ and washedwith brine. The organic layer was dried over MgSO₄ and filtered. Afterconcentration in vacuo, the residue was purified by preparative TLC(CH₂Cl₂/MeOH=10/1) to afford 224 mg (71%) of the title compound.

[3041]¹H-NMR (DMSO-d₆) δ: 10.82 (1H, s), 8.54 (2H, s), 7.79 (2H, d,J=8.3 Hz), 7.51-7.40 (6H, m), 7.06 (1H, s), 6.91 (1H, t, J=5.5 Hz),3.29-3.24 (2H, m), 2.80-2.76 (2H, m), 2.48 (3H, s), 2.38 (3H, s), 2.36(3H, s).

[3042] MS (ESI) m/z: 479 ([M+H]⁺), 477 ([M−H]⁻).

[3043] Step 2.2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridinedi-hydrochloride

[3044] The title compound was prepared according to the proceduredescribed in Example 240 from2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine.

[3045] MS (ESI) m/z: 479 ([M+H]⁺), 477 ([M−H]⁻).

Example 3025,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(methylsulfanyl-3H-imidazo[4,5-b]pyridine

[3046] A mixture ofN-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(110 mg, 0.24 mmol), di-2-pyridylthiocarbonate (68 mg, 0.29 mmol), andTHF (5 ml) was stirred at room temperature for 3 days. The mixture wasdiluted with CH₂Cl₂ and washed with 0.1M HCl and brine. The organicfraction was dried over MgSO₄, and filtered. The solvent was removed togiveN-[({2-[4-[(5,7-dimethyl-2-sulfanyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl}-4-methylbenzenesulfonamide[MS (ESI) m/z: 496 ([M+H]⁺), 494 ([M−H]⁻)]. This was dissolved with THF(2 ml), then 1M NaOMe in MeOH (0.49 ml) and MeI (45 μl, 0.73 mmol) wasadded to the mixture at room temperature. After 1 hour, the mixture wasevaporated in vacuo and the residue was purified by preparative TLC(CH₂Cl₂/MeOH=10/1) to afford 31 mg (25%) of the title compounds.

[3047]¹H-NMR (CDCl₃) δ: 7.86 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.1 Hz),7.22-7.16 (4H, m), 6.88 (1H, s), 6.02 (1H, t, J=5.6 Hz), 3.51-3.45 (2H,m), 2.83 (2 h, t, J=6.2 Hz), 2.67 (3H, s), 2.62 (3H, s), 2.42 (3H, s),2.417 (3H, s).

[3048] MS (ESI) m/z: 510 ([M+H]⁺), 508 ([M−H]⁻).

Example 3035,7-Dimethyl-2-(methylamino)-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[3049] A mixture ofN-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(300 mg, 0.66 mmol), methylisothiocyanate (56 μl, 0.86 mmol), and THF (6ml) was stirred at room temperature for 3 days. The solvent was removedto giveN-{[(2-{4-[(4,6-dimethyl-{[(methylamino)carbonothioyl]amino}-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide[MS (ESI) m/z: 527 ([M+H]⁺), 525 ([M−H]⁻)]. This was dissolved with MeCN(4 ml) and treated with MeI (54 μl) at 0° C. for 20 hours. Afterconcentration under reduced pressure, the residue was purified bypreparative TLC (EtOAc/EtOH=20/1) to afford 170 mg (52%) of the titlecompounds.

[3050]¹H-NMR (CD₃OD) δ: 7.72 (2H, d, J=8.3 Hz), 7.24 (4H, d, J=7.9 Hz),7.15 (2H, d, J=8.4 Hz), 6.70 (1H, s), 3.28 (2H, t, J=7.0 Hz), 2.90 (3H,s), 2.72 (2H, t, J=7.0 Hz), 2.41 (3H, s), 2.26 (3H, s), 2.24 (3H, s).

[3051] MS (ESI) m/z: 493 ([M+H]⁺), 491 ([M−H]⁻).

Example 3045,7-Dimethyl-2-(methylamino)-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridinemono-hydrochloride

[3052] The title compound was prepared according to the proceduredescribed in Example 240 from5,7-dimethyl-2-(methylamino)-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridinehydrochloride.

[3053] MS (ESI) m/z: 493 ([M+H]⁺), 491 ([M−H]⁻).

Example 305N-[5,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]acetamide

[3054]2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(73 mg) was treated with pyridine (1 ml) and Ac₂O (0.2 ml) at roomtemperature for 3 hours. After evaporation in vacuo, the residue waspurified by preparative TLC (hexane/acetone=1/1) to afford 4 mg (5%) ofthe title compounds.

[3055]¹H-NMR (CDCl₃) δ: 7.79 (2H, d, J=8.4 Hz), 7.34-7.22 (7H, m), 7.04(1H, s), 6.30 (1H, br.s), 3.51-3.48 (2H, m), 2.87-2.83 (2H, m), 2.66(3H, s), 2.53 (3H, s), 2.42 (3H, s), 2.26 (3H, s).

[3056] MS (ESI) m/z: 521 ([M+H]⁺), 519 ([M−H]⁻).

Example 3065,7-Dimethyl-2-(dimethylamino)-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

[3057] To a stirred solution of2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine(70 mg) in THF (1 ml) was added NaH (21 mg, 0.88 mmol) at roomtemperature. After 10 min, MeI (27 μl) was added to the mixture andstirred at room temperature for 2 days. The mixture was poured intoice-water and extracted with CH₂Cl₂, and the organic fraction was driedover MgSO₄, then filtered. After removal of solvent by evaporation, theresidue was purified by preparative TLC (CH₂Cl₂/MeOH=10/1) to afford 27mg (36%) of the title compounds.

[3058]¹H-NMR (CDCl₃) δ: 7.86 (2H, d, J=8.4 Hz), 7.32-7.24 (4H, m), 7.16(2H, d, J=8.4 Hz), 6.77 (1H, s), 6.04 (1H, t, J=5.7 Hz), 3.50-3.44 (2H,m), 2.78 (2H, t, J=6.3 Hz), 2.71 (6H, s), 2.55 (3H, s), 2.41 (3H, s),2.34 (3H, s).

[3059] MS (ESI) m/z: 507 ([M+H]⁺), 505 ([M−H]⁻).

Example 3072-[4-(2-Amino-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3060] Step 1.2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3061] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol.

[3062]¹H-NMR (CDCl₃) δ: 9.55 (1H, s), 7.89 (2H, d, J=8.3 Hz), 7.54 (2H,d, J=8.6 Hz), 7.32 (2H, d, J=8.6 Hz), 7.11 (2H, d, J=8.4 Hz), 6.54 (1H,s), 4.28 (2H, t, J=7.0 Hz), 2.88 (2H, t, J=7.0 Hz), 2.55 (3H, s), 2.43(6H, s).

[3063] MS (ESI) m/z: 485 ([M+H]⁺), 483 ([M−H]⁻).

[3064] Step 2.2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3065] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate.

[3066]¹H-NMR (CDCl₃) δ: 7.82 (2H, d, J=8.3 Hz), 7.25 (2H, d, J=8.3 Hz),6.93 (2H, d, J=8.4 Hz), 6.84 (2H, d, J=8.4 Hz), 6.66 (1H, s), 4.22 (2H,t, J=6.6 Hz), 2.77 (2H, t, J=6.6 Hz), 2.39 (3H, s), 2.37 (3H, s), 2.22(3H, s).

[3067] MS (ESI) m/z: 455 ([M+H]⁺), 453 ([M−H]⁻).

[3068] Step 3.2-[4-(2-amino-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3069] The title compound was prepared according to the proceduredescribed in Example 127 from2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate.

[3070]¹H-NMR (DMSO-d₆) δ: 7.76 (2H, d, J=8.3 Hz), 7.42-7.35 (6H, m),6.78 (1H, s), 6.61 (1H, br.s), 4.22 (2H, t, J=6.6 Hz), 2.92 (2H, d,J=6.6 Hz), 2.373 (3H, s), 2.365 (3H, s), 2.32 (3H, s).

[3071] MS (ESI) m/z: 480 ([M+H]⁺), 478 ([M−H]⁻).

Example 3082-{4-[5,7-Dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3072] The title compound was prepared according to the proceduredescribed in Example 129 from2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate.

[3073]¹H-NMR (DMDO-d₆) δ: 7.78 (2H, d, J=8.1 Hz), 7.43-7.33 (7H, m),6.77 (1H, s), 6.43 (1H, br.s), 4.25 (2H, t, J=6.6 Hz), 2.93 (2H, t,J=6.6 Hz), 2.88 (3H, s), 2.41 (3H, s), 2.37 (3H, s), 2.31 (3H, s).

[3074] MS (ESI) m/z: 494 ([M+H]⁺), 492 ([M−H]⁻).

Example 3092-{4-[5,7-Dimethyl-2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3075] The title compound was prepared according to the proceduredescribed in Example 128 from2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate.

[3076]¹H-NMR (CDCl₃) δ: 7.92 (2H, d, J=8.4 Hz), 7.36-7.22 (6H, m), 6.88(1H, s), 4.32 (2H, t, J=6.6 Hz), 2.93 (2H, t, J=6.6 Hz), 2.72 (3H, s),2.62 (3H, s), 2.48 (3H, s), 2.41 (3H, s).

[3077] MS (ESI) m/z: 511 ([M+H]⁺), 509 ([M−H]⁻).

Example 3102-{4-[5,7-Dimethyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3078] To a stirred solution of2-{4-[5,7-dimethyl-2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate (100 mg, 0.20 mmol) in AcOH (1 ml) wasadded a solution of KMnO₄ (62 mg, 0.39 mmol) in water (2 ml) at roomtemperature. After 1 hour, the mixture was poured into ice-sat. NaHCO₃aq. and extracted with CH₂Cl₂. The organic layer was dried over MgSO₄,and the filtered. After concentration in vacuo, the residue was purifiedby preparative TLC (CH₂Cl₂/MeOH=10/1) to afford 70 mg (66%) of the titlecompounds.

[3079]¹H-NMR (CDCl₃) δ: 7.91 (2H, d, J=8.4 Hz), 7.47 (2H, d, J=8.2 Hz),7.34-7.26 (4H, m), 7.08 (1H, s), 4.35 (2H, t, J=6.7 Hz), 3.45 (3H, s),2.96 (2H, t, J=6.7 Hz), 2.68 (3H, s), 2.55 (3H, s), 2.42 (3H, s).

[3080] MS (ESI) m/z: 543 ([M+H]⁺), 541 ([M−H]⁻).

Example 3115-Acetyl-2-(methylamino)-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[3081] The title compound was prepared according to the proceduredescribed in Example 129 fromN-{[(2-{4-[(4-acetyl-2-aminophenyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide.

[3082]¹H-NMR (CDCl₃) δ: 8.06 (1H, s), 7.75-7.66 (3H, m), 7.38-7.26 (6H,m), 6.89 (1H, d, J=8.3 Hz), 6.60 (1H, br.s), 3.55 (2H, dd, J=12.5 and6.6 Hz), 3.08 (3H, s), 2.91 (2H, t, J=6.6 Hz), 2.61 (3H, s), 2.38 (3H,s).

[3083] MS (ESI) m/z: 506 ([M+H]⁺), 504 ([M−H]⁻).

Example 3122-{4-[6-Chloro-2-(3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3084] Step 1.2-{4-[6-chloro-2-(3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3085] The title compound was prepared according to the proceduredescribed in Example 138 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl) phenyl]amino}phenyl)ethanol.

[3086]¹H-NMR (CDCl₃) δ: 8.70 (1H, dd, J=2.2 and 0.7 Hz), 8.62 (1H, dd,J=4.5 and 1.7 Hz), 8.23 (1H, s), 8.01-7.97 (1H, m), 7.45 (2H, dd, J=6.5and 2.2 Hz), 7.37-7.24 (7H, m), 3.97 (2H, t, J=6.6 Hz), 2.99 (2H, t,J=6.6 Hz).

[3087] MS (ESI) m/z: 418 ([M+H]⁺), 476 ([M+CF₃CO₂]⁻).

[3088] Step 2.2-{4-[6-chloro-2-(3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3089] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[6-chloro-2-(3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol.

[3090]¹H-NMR (CDCl₃) δ: 8.73 (1H, dd, J=4.9 and 1.8 Hz), 8.40-8.36 (1H,m), 8.23 (1H, s), 7.91 (1H, dd, J=2.2 and 0.7 Hz), 7.84-7.80 (2H, m),7.49-7.43 (2H, m), 7.31-7.17 (6H, m), 4.44 (2H, t, J=6.2 Hz), 3.02 (2H,t, J=6.2 Hz), 2.41 (3H, s).

[3091] MS (ESI) m/z: 615 ([M+H]⁺), 613 ([M−H]⁻).

Example 3132-{4-[6-Chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3092] Step 1.2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3093] The title compound was prepared according to the proceduredescribed in Example 138 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl) phenyl]amino}phenyl)ethanol.

[3094]¹H-NMR (CDCl₃) δ: 8.60 (2H, dd, J=4.6 and 1.7 Hz), 8.25 (1H, s),7.49-7.44 (4H, m), 7.37 (1H, s), 7.27-7.23 (2H, m), 4.00 (2H, t, J=6.4Hz), 3.02 (2H, t, J=6.4 Hz).

[3095] MS (ESI) m/z: 418 ([M+H]⁺), 476 ([M+CF₃CO₂]⁻).

[3096] Step 2.2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3097] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol.

[3098]¹H-NMR (CDCl₃) δ: 8.60 (2H, dd, J=4.8 and 1.5 Hz), 8.27 (1H, s),7.89 (2H, d, J=8.3 Hz), 7.44-7.18 (9H, m), 4.39 (2H, t, J=6.4 Hz), 3.03(2H, t, J=6.4 Hz), 2.40 (3H, s).

[3099] MS (ESI) m/z: 615 ([M+H]⁺), 613 ([M−H]⁻).

Example 3142-{4-[6-Chloro-2-(2-methylphenyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3100] Step 1.2-{4-[6-chloro-2-(2-methylphenyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3101] The title compound was prepared according to the proceduredescribed in Example 138 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl) phenyl]amino}phenyl)ethanol.

[3102]¹H-NMR (CDCl₃) δ: 8.22 (1H, s), 7.47 (1H, s), 7.33-7.10 (8H, m),3.89 (2H, t, J=6.4 Hz), 2.89 (2H, t, J=6.4 Hz), 2.20 (3H, s).

[3103] MS (ESI) m/z: 431 ([M+H]⁺).

[3104] Step 2.2-{4-[6-chloro-2-(2-methylphenyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3105] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[6-chloro-2-(2-methylphenyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol.

[3106]¹H-NMR (CDCl₃) δ: 8.24 (1H, s), 7.78 (2H, d, J=8.2 Hz), 7.46 (1H,s), 7.35-7.09 (8H, m), 7.00 (2H, d, J=8.4 Hz), 4.27 (2H, t, J=6.8 Hz),2.88 (2H, t, J=6.8 Hz), 2.41 (3H, s), 2.11 (3H, s).

[3107] MS (ESI) m/z: 628 ([M+H]⁺), 489 ([M+CH₃CO₂]⁻)

Example 3152-{4-[6-Chloro-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3108] Step 1.2-{4-[6-chloro-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3109] The title compound was prepared according to the proceduredescribed in Example 138 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl) phenyl]amino}phenyl)ethanol.

[3110]¹H-NMR (CDCl₃) δ: 8.23 (1H, s), 7.75 (1H, d, J=3.1 Hz), 7.47-7.45(3H, m), 7.36-7.27 (3H, m), 3.99 (2H, t, J=6.4 Hz), 3.03 (2H, t, J=6.4Hz).

[3111] MS (ESI) m/z: 424 ([M+H]⁺), 482 ([M+CH₃CO₂]⁻)

[3112] Step 2.2-{4-[6-chloro-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3113] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[6-chloro-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol.

[3114]¹H-NMR (CDCl₃) δ: 8.23 (1H, s), 7.91 (2H, d, J=8.4 Hz), 7.74 (1H,d, J=3.1 Hz), 7.46 (1H, d, J=3.1 Hz), 7.38-7.26 (7H, m), 4.40 (2H, t,J=6.8 Hz), 3.04 (2H, t, J=6.8 Hz), 2.42 (3H, s).

[3115] MS (ESI) m/z: 621 ([M+H]⁺), 619 ([M−H]⁻).

Example 3162-{4-[6-Chloro-2-(1H-imidazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenylethyl(4-methylphenyl)sulfonylcarbamate

[3116] Step 1.2-{4-[6-chloro-2-(1H-imidazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3117] The title compound was prepared according to the proceduredescribed in Example 138 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl) phenyl]amino}phenyl)ethanol.

[3118]¹H-NMR (CDCl₃/CD₃OD=4/1) δ: 8.09 (1H, s), 7.65 (1H, s), 7.50 (2H,d, J=8.7 Hz), 7.33 (2H, d, J=8.2 Hz), 7.25 (1H, s), 6.91 (1H, s), 3.93(2H, t, J=6.4 Hz), 3.00 (2H, t, J=6.4 Hz).

[3119] MS (ESI) m/z: 407 ([M+H]⁺), 405 ([M−H]⁻).

[3120] Step 2.2-{4-[6-chloro-2-(1H-imidazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3121] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[6-chloro-2-(1H-imidazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol.

[3122] MS (ESI) m/z: 604 ([M+H]⁺), 602 ([M−H]⁻).

Example 317 2-[4-(5,6-Dimethyl-1H-benzimidazol-1-yl)phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3123] Step. 1 4-(2-hydroxyethyl)phenylboronic acid

[3124] To a stirred solution of 4-bromophenethylalcohol (5.00 g, 24.9mmol) in THF (80 ml) was added a solution of 1.5M n-BuLi in hexane (39.8ml, 59.7 mmol) at −78° C. over 30 min. After 1 hour, a solution ofB(O^(i)Pr)₃ (8.61 ml, 37.3 mmol) in THF (20 ml) was added slowly to themixture at −78° C. The resultant mixture was warmed to room temperature,and treated with 2M HCl (100 ml) for 1 hour. This was extracted withCH₂Cl₂ and dried over MgSO₄, then filtered. After evaporation in vacuo,the residue was purified by silica-gel column chromatography elutingwith CH₂Cl₂/MeOH=20/1 to afford 2.61 g (63%) of the title compound.

[3125]¹H-NMR (CD₃OD) δ: 7.64-7.48 (2H, m), 7.19-7.13 (2H, m), 3.70 (2H,t, J=7.2 Hz), 2.77 (2H, t, J=7.2 Hz).

[3126] MS (ESI) m/z: 165 ([M−H]⁻).

[3127] Step 2.4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronicacid

[3128] 4-(2-hydroxyethyl)phenylboronic acid (1.00 g, 6.02 mmol) wastreated with pTsNCO (1.01 ml, 6.63 mmol) and pyridine (90 ml) at roomtemperature for 2 hours. The mixture was poured into ice-2M HCl andextracted with EtOAc. The organic layer was dried over MgSO₄, andfiltered. After removal of solvent, the residue was purified bysilica-gel column chromatography eluting with CH₂Cl₂/MeOH=20/1 to afford2.20 g (quant.) of the title compound.

[3129]¹ ¹H-NMR (DMSO-d₃) δ: 11.95 (1H, br.s), 7.97 (1H, s), 7.75-7.67(2H, m), 7.40 (2H, d, J=8.6 Hz), 7.13 (2H, d, J=7.7 Hz), 4.18 (2H, t,J=6.6 Hz), 2.81 (2H, t, J=6.6 Hz), 2.40 (3H, s).

[3130] MS (ESI) m/z: 381 ([M+NH₄]⁺), 362 ([M−H]⁻).

[3131] Step 3. 2-[4-(5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3132] A mixture of4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronicacid (100 mg, 0.28 mmol), 5,6-dimethylbenzimidazole (40 mg, 0.28 mmol),Cu(OAc)₂ (60 mg, 0.33 mmol), triethylamine (115 μl, 0.83 mmol), MS4A(100 mg), and CH₂Cl₂ (4 ml) was stirred at room temperature for 1 week.After filtration through a bed of celite, the filtrate was diluted withCH₂Cl₂, and washed with water. The organic fraction was dried over MgSO₄and filtered. After concentration under reduced pressure, the residuewas purified by preparative TLC (CH₂Cl₂/MeOH=10/1) to afford 28 mg (22%)of the title compound.

[3133]¹H-NMR (CDCl₃) δ: 7.82 (2H, d, J=8.4 Hz), 7.72 (1H, s), 7.57 (1H,s), 7.33 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.4 Hz), 7.07 (1H, s), 7.01(2H, d, J=8.4 Hz), 4.39 (2H, t, J=6.1 Hz), 2.94 (2H, t, J=6.1 Hz), 2.42(3H, s), 2.39 (3H, s), 2.26 (3H, s).

[3134] MS (ESI) m/z: 464 ([M+H]⁺), 462 ([M−H]⁻).

Example 3186-Chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-bevzimidazole

[3135] Step 1.6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carbonitrile

[3136] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile(Example 111, step 4).

[3137]¹H-NMR (CDCl₃) δ 8.07 (1H, s), 7.50 (2H, d, J=8.4 Hz), 7.30 (2H,d, J=8.4 Hz), 7.19 (1H, s), 3.83 (2H, t, J=7.1 Hz), 3.22 (2H, t, J=7.1Hz), 2.79 (2H, q, J=7.5 Hz), 1.37 (3H, t, J=7.5 Hz).

[3138] Step 2.1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile

[3139] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carbonitrile(step 1).

[3140]¹H-NMR (CDCl₃) δ 8.07 (1H, s), 7.49 (2H, d, J=8.4 Hz), 7.29 (2H,d, J=8.4 Hz), 7.18 (1H, s), 3.64 (2H, t, J=7.0 Hz), 3.04 (2H, t, J=7.0Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).

[3141] Step 3.1-[4-(2-Aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile

[3142] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile(step 2).

[3143]¹H-NMR (CDCl₃) δ 8.06 (1H, s), 7.46 (2H, d, J=8.1 Hz), 7.26 (2H,d, J=8.1 Hz), 7.19 (1H, s), 3.09 (2H, t, J=7.1 Hz), 2.89 (2H, t, J=7.1Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).

[3144] Step 4.6-Chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[3145] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile(step 3).

[3146] mp 219-224° C.; IR (KBr) v: 3388, 2229, 1708, 1618, 1514, 1466,1344, 1161, 1089 cm⁻¹.

[3147] MS (ESI) m/z 522 (M+H)⁺, 520 (M−H)⁻; ¹H-NMR (DMSO-d₆) δ 8.38 (1H,s), 7.77 (2H, d, J=8.2 Hz), 7.31-7.49 (6H, m), 7.32 (1H, s), 6.53 (1H,br.s), 3.26-3.28 (2H, m), 2.69-2.81 (4H, m), 2.35 (3H, s), 1.25 (3H, t,J=7.6 Hz).

Example 3196-Chloro-5-(dimethylamino)-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[3148] Step 1.N-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-N,N-dimethylamine

[3149] A mixture of6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine(Example 110, step 6, 100 mg, 0.3 mmol) and NaBH₄ (153 mg, 4 mmol) inTBF (5 ml) was added to the mixture of 38% folmaldehyde (0.5 ml, 5.6mmol) and 3M aqueous H₂SO₄ (0.4 ml, 0.12 mmol) at 0° C. The mixture wasstirred at room temperature for 5 h. The reaction mixture was pouredinto water, and extracted with ethyl acetate (100 ml). The organic layerwas washed with brine (50 ml), then dried (Na₂SO₄). After removal ofsolvent, the crude product was purified by flash column chromatographyeluting with hexane/ethyl acetate (1:2) to afford 48 mg (46%) of thetitle compound as white solids.

[3150] MS (EI) m/z: 361 (M⁺).

[3151]¹H-NMR (CDCl₃) δ: 7.54 (1H, s), 7.44 (2H, d, J=8.3 Hz), 7.29 (2H,d, J=8.3 Hz), 7.13 (1H, s), 3.82 (2H, t, J=7.0 Hz), 3.19 (2H, t, J=7.0Hz), 2.82 (6H, s), 2.75 (2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.6 Hz).

[3152] Step 2.N-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}-N,N-dimethylamine

[3153] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 fromN-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-N,N-dimethylamine(step 1).

[3154]¹H-NMR (CDCl₃) δ: 7.54 (1H, s), 7.43 (2H, d, J=8.2 Hz), 7.29 (2H,d, J=8.2 Hz), 7.12 (1H, s), 3.62 (2H, t, J=7.0 Hz), 3.01 (2H, t, J=7.0Hz), 2.82 (6H, s), 2.75 (2H, q, J=7.6 Hz), 1.34 (2H, t, J=7.6 Hz).

[3155] Step 3.N-{1-[4-(2-aminoethyl)phenYl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}-N,N-dimethylamine

[3156] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 fromN-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}-N,N-dimethylamine(step 2).

[3157]¹H-NMR (CDCl₃) δ: 7.54 (1H, s), 7.41 (2H, d, J=8.1 Hz), 7.27 (2H,d, J=8.1 Hz), 7.13 (1H, s), 3.08 (2H, t, J=6.9 Hz), 2.87 (2H, t, J=6.9Hz), 2.82 (6H, s), 2.75 (2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.6 Hz).

[3158] Step 4.6-chloro-5-(dimethylamino)-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[3159] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 fromN-{1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}-N,N-dimethylamine(step 3).

[3160] m.p.: 108-114° C.

[3161] MS (ESI) m/z: 540 (MH⁺), 538 ([M−H]⁻).

[3162]¹H-NMR (CDCl₃) δ: 7.73 (2H, d,=8.0 Hz), 7.54 (1H, s), 7.25-7.39(6H, m), 7.11 (1H, s), 6.73 (1H, br.s), 3.58 (2H, q, J=6.9 Hz), 2.94(2H, t, J=6.9 Hz), 2.71-2.82 (8H, m), 2.40 (3H, s), 1.33 (3H, t, J=7.6Hz).

Example 3206-Chloro-2-ethyl-5-(methylamino)-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[3163] Step 1.6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylformamide

[3164] A solution of acetic anhydride (0.14 ml) in THF (5 ml) was addedformic acid (0.06 ml, 1.65 mmol) at 0° C. under nitrogen and the mixturewas stirred at 60° C. for 2 h. Then the mixture was recooled to 0° C.and was added6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine(Example110, step 6, 100 mg, 0.3 mmol) in THF (2 ml). The mixture was stirred atroom temperature for 2 h. The volatile component was removed underreduced pressure, and the residue was dissolved with ethyl acetate (100ml). The organic layer was washed with 2N aqueous NaOH (50 ml), brine(50 ml), then dried (Na2SO4). After removal of solvent, the crudeproduct was purified by flash column chromatography eluting withhexane/ethyl acetate (1:10) to afford 68 mg (67%) of the title compoundas pale yellow solids.

[3165] MS (EI) m/z: 361 (M⁺).

[3166]¹H-NMR (CDCl₃) δ: 8.53-8.76 (1H, br.s), 7.66 (1H, s), 7.44-7.48(2H, m), 7.26-7.31 (2H, m), 7.18 (1H, s), 3.83 (2H, t, J=6.9 Hz), 3.20(2H, t, J=6.9 Hz), 2.78 (2H, q, J=7.4 Hz), 1.32-1.39 (3H, m).

[3167] Step 2.N-16-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl)-N-methylamine

[3168] A solution of(6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylformamide,step 1, 112 mg, 0.3 mmol) in THF (15 ml) was added Me₂S BH₃ (0.07 ml,0.77 mmol) under nitrogen at room temperature. The mixture was refluxedfor 1 h. Then the mixture was cooled to room temperature and was addedmethanol (3 ml) and 2N aqueous HCl (12 ml). The mixture was stirred at70° C. for 30 min. The volatile component was removed under reducedpressure, and the residue was dissolved with ethyl acetate (100 ml). Theorganic layer was washed with saturated aqueous NaHCO₃ (50 ml), brine(50 ml), then dried (Na2SO4). After removal of solvent, the crudeproduct was purified by flash column chromatography eluting withhexane/ethyl acetate (1:4) to afford 93 mg (87%) of the title compoundas white solids.

[3169] MS (EI) m/z: 347 (M⁺).

[3170]¹H-NMR (CDCl₃) δ: 7.42 (2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz),7.04 (1H, s), 7.03 (1H, s), 3.81 (2H, t, J=6.9 Hz), 3.18 (2H, t, J=6.9Hz), 2.95 (3H, s), 2.75 (2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz).

[3171] Step 3.N-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}-N-methylamine

[3172] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 fromN-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-N-methylamine(step 2).

[3173]¹H-NMR (CDCl₃) δ: 7.42 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz),7.04-7.03 (2H, m), 4.19 (1H, br.s), 3.61 (2H, t, J=7.0 Hz), 3.00 (2H, t,J=7.0 Hz), 2.95 (3H, s), 2.75 (2H, q, J=7.6 Hz), 1.33 (3H, t, J=7.6 Hz).

[3174] Step 4.N-{1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}-N-methylamine

[3175] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 fromN-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}-N-methylamine(step 3).

[3176]¹H-NMR (CDCl₃) δ: 7.39 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz),7.06 (1H, s), 7.03 (1H, s), 3.64 (2H, br.s), 3.15 (2H, t, J=7.2 Hz),2.94-2.99 (5H, m), 2.73 (2H, q, J=7.5 Hz), 1.32 (3H, t, J=7.5 Hz).

[3177] Step 5.6-chloro-2-ethyl-5-(methylamino)-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[3178] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 fromN-{1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl}-N-methylamine(step 4).

[3179] m.p.: 95-100° C.

[3180] MS (ESI) m/z: 526 (MH⁺), 524 ([M−H]⁻).

[3181]¹H-NMR (CDCl₃) δ: 7.73 (2H, d, J=8.4 Hz), 7.23-7.36 (7H, m), 7.03(1H, s), 3.57 (2H, t, J=6.6 Hz), 2.89-2.94 (5H, m), 2.73 (2H, q, J=7.4Hz), 1.32 (3H, t, J=7.4 Hz).

Example 3214-Cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[3182] Step 1. 3-chloro-2-nitrobenzamide

[3183] A mixture of 3-chloro-2-nitro-benzoic acid (1 g, 4.9 mmol) andthionyl chloride (9 ml) was stirred at 80° C. for 1 h. The thionylchloride was removed under reduced pressure, and the residue wasdissolved with dichloromethane (15 ml). The mixture was cooled to 0° C.and was added 30% aqueous NH3 (2 ml) dropwise. The mixture was stirredat 0° C. for 25 min. The reaction mixture was poured into water andextracted with ethyl acetate (300 ml). The organic layer was washed withsaturated aqueous Na₂CO₃ (100 ml), and brine (100 ml). This organicphase was dried (Na₂SO₄) and concentrated under reduced pressure to give1.2 g (quant.) of the title compound as pale orange solids.

[3184]¹H-NMR (CDCl₃) δ: 7.68-7.92 (3H, m).

[3185] Step 2. 3-chloro-2-nitrobenzonitrile

[3186] A solution of 3-chloro-2-nitrobenzamide (step 1, 1.2 g, 4.9 mmol)in DMF (8 ml) was added thionyl chloride (2 ml, 24.8 mmol) in DMF (3 ml)dropwise at room temperature. The mixture was stirred at 120° C. for 2.5h. The mixture was poured into ice-water and extracted with ethylacetate (200 ml). The organic layer was washed with saturated aqueousNaHCO₃ (100 ml), brine (100 ml), then dried (MgSO4), and concentrated.The residue was purified by flash chromatography eluting withhexane/ethyl acetate (3:1/1:2) to give 1 g (quant.) of the titlecompound as pale yellow solids.

[3187]¹H-NMR (CDCl₃) δ: 7.61-7.68 (1H, m), 7.74-7.78 (2H, m).

[3188] Step 3. 2-[4-(3-Cyano-2-nitroanilino)phenyl]ethanol

[3189] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 3-chloro-2-nitrobenzonitrile (step2) and 4-aminophenylethyl alcohol.

[3190] MS (EI) m/z: 283 (M⁺).

[3191]¹H-NMR (CDCl₃) δ: 9.37 (1H, br.s), 7.15-7.41 (7H, m), 3.91 (2H, t,J=6.4 Hz), 2.91 (2H, t, J=6.4 Hz).

[3192] Step 4. 2-amino-3-[4-(2-hydroxyethyl)anilino]benzonitrile

[3193] The title compound was prepared according to the proceduredescribed in step 2 of Example 40 from2-[4-(3-Cyano-2-nitroanilino)phenyl]ethanol (step 3).

[3194] MS (EI) m/z: 253 (M⁺).

[3195]¹H-NMR (CDCl₃) δ: 7.22-7.28 (2H, m), 7.10 (2H, d, J=8.4 Hz),6.69-6.75 (3H, m), 5.13 (1H, br.s), 4.54 (2H, br.s), 3.84 (2H, t, J=6.4Hz), 2.80 (2H, t, J=6.4 Hz).

[3196] Step 5. 2-[4-(4-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[3197] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-amino-3-[4-(2-hydroxyethyl)anilino]benzonitrile (step 4).

[3198] TLC, Rf=0.6, hexane:ethyl acetate (1:1).

[3199] Step 6.2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-4-carbonitrile

[3200] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(4-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step5).

[3201] MS (EI) m/z: 291 (M⁺).

[3202]¹H-NMR (CDCl₃) δ: 7.58 (1H, d, J=6.3 Hz), 7.49 (2H, d, J=8.3 Hz),7.19-7.32 (4H, m), 4.01 (2H, t, J=6.4 Hz), 3.02 (2H, t, J=6.4 Hz), 2.86(2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz).

[3203] Step 7.1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile

[3204] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-4-carbonitrile(step 6).

[3205]¹H-NMR (DMSO-d₆) δ: 7.72 (1H, dd, J=1.2 Hz, 7.4 Hz), 7.51-7.60(4H, m), 7.30-7.42 (2H, m), 3.97 (2H, t, J=7.0 Hz), 3.18 (2H, t, J=7.0Hz), 2.79 (2H, q, J=7.6 Hz), 1.26 (3H, t, J=7.6 Hz).

[3206] Step 8.1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile

[3207] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile(step 7).

[3208]¹H-NMR (CDCl₃) δ: 7.59 (1H, dd, J=1.2 Hz, 7.3 Hz), 7.48 (2H, d,J=8.0 Hz), 7.19-7.32 (4H, m), 3.63 (2H, t, J=6.6 Hz), 3.03 (2H, t, J=6.6Hz), 2.84 (2H, q, J=7.6 Hz), 1.31 (3H, t, J=7.6 Hz).

[3209] Step 9.1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile

[3210] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile (step8).

[3211]¹H-NMR (CDCl₃) δ: 7.58 (1H, dd, J=1.3 Hz, 7.4 Hz), 7.44 (2H, d,J=8.2 Hz), 7.19-7.32 (4H, m), 3.08 (2H, t, J=6.7 Hz), 2.81-2.93 (4H, m),1.33 (3H, t, J=7.5 Hz).

[3212] Step 10.4-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[3213] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile (step9).

[3214] m.p.: 95-103° C.

[3215] IR (KBr) v: 2225, 1676, 1516, 1433, 1340, 1161, 1091, 794, 663cm⁻¹.

[3216] MS (ESI) m/z: 488 (MH⁺), 486 ([M−H]⁻).

[3217]¹H-NMR (CDCl₃) δ: 7.72 (2H, d, J=8.1 Hz), 7.59 (1H, d, J=7.0 Hz),7.42 (2H, d, J=8.1 Hz), 7.18-7.32 (6H, m), 6.72 (1H, br.s), 3.57 (2H, t,J=7.1 Hz), 2.96 (2H, t, J=7.1 Hz), 2.85 (2H, q, J=7.6 Hz), 2.41 (3H, s),1.33 (3H, t, J=7.6 Hz).

Example 3222-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-4-carboxamide

[3218] Step 1.2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-4-carboxamide

[3219] To a stirred suspension of2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4,820 mg, 3.3 mmol) in toluene (30 ml) was added dropwise propionylchloride (630 mg, 6.8 mmol) at 0° C., and the reaction mixture wasrefluxed for 1.5 h. After cooling, the mixture was poured into water (50ml) and extracted with ethyl acetate (100 ml). The organic layer waswashed with 2N aqueous NaOH (50 ml) and brine (50 ml), then dried(Na2SO4). The solvent was removed under reduced pressure and the residuewas dissolved with THF(20 ml) and methanol (20 ml). The mixture wasadded 4N aqueous LiOH (10 ml) and stirred at room temperature for 14 h.The mixture was evaporated. The residue was dissolved with ethyl acetate(100 ml) and washed with water (50 ml). The organic layer was washedwith brine (50 ml), and dried (Na2SO4). After removal of solvent, thecrude product was purified by flash column chromatography eluting withhexane/ethyl acetate (1:2/1:5/0:1) to afford 260 mg (26%) of the titlecompound as white solids.

[3220] MS (EI) m/z: 309 (M⁺).

[3221]¹H-NMR (CDCl₃) δ: 9.81 (1H, br.s), 8.13 (1H, dd, J=2.0 Hz, 7.0Hz), 7.47 (2H, d, J=8.0 Hz), 7.25-7.31 (4H, m), 5.99 (1H, br.s), 4.00(2H, t, J=6.4 Hz), 3.01 (2H, t, J=6.4 Hz), 2.82 (2H, q, J=7.6 Hz), 1.37(3H, t, J=7.6 Hz).

[3222] Step2.1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carboxamide

[3223] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-[4-(6-chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]ethanol (step1).

[3224]¹H-NMR (DMSO-d₆) δ: 9.29 (1H, br.s), 7.81-7.91 (1H, m), 7.79 (1H,br.s), 7.49-7.60 (4H, m), 7.24-7.33 (2H, m), 3.97 (2H, t, J=6.8 Hz),3.18 (2H, t, J=6.8 Hz), 2.80 (2H, q, J=7.5 Hz), 1.27 (3H, t, J=7.5 Hz).

[3225] Step3.1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carboxamide

[3226] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide(step 2).

[3227]¹H-NMR (DMSO-d₆) 8:9.29 (1H, br.s), 7.89 (1H, d, J=7.3 Hz), 7.79(1H, br.s), 7.51-7.59 (4H, m), 7.22-7.33 (2H, m), 3.68 (2H, t, J=6.6Hz), 3.01 (2H, t, J=6.6 Hz), 2.77 (2H, q, J=7.5 Hz), 1.27 (3H, t, J=7.5Hz).

[3228] Step 4.1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carboxamide

[3229] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide(step 3).

[3230]¹H-NMR (DMSO-d₆) δ: 9.30 (1H, br.s), 7.89 (1H, d, J=6.5 Hz), 7.81(1H, br.s), 7.48-7.49 (4H, m), 7.26-7.30 (2H, m), 2.77-2.89 (6H, m),1.28 (3H, t, J=6.4 Hz).

[3231] Step 5.2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-4-carboxamide

[3232] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide(step 4).

[3233] m.p.: 208-214° C.

[3234] IR (KBr) v: 3336, 1664, 1589, 1508, 1406, 1342, 1168, 976 cm⁻¹.

[3235] MS (ESI) m/z: 506 (MH⁺), 504 ([M−H]⁻).

[3236]¹H-NMR (DMSO-d₆) δ: 9.29 (1H, br.s), 7.89 (1H, dd, J=1.3 Hz, 7.2Hz), 7.75-7.79 (3H, m), 7.22-7.49 (8H, m), 6.54 (1H, br.s), 2.75-2.83(4H, m), 2.35 (3H, s), 1.27 (3H, t, J=7.4 Hz).

Example 3236-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(methylsulfonyl)-1H-benzimidazole

[3237] Step 1. 1,5-dichloro-2-(methylsulfinyl)-4-nitrobenzene

[3238] A mixture of (2,4-dichloro-phenyl)-methyl sulfone (Ono Mitsunori,Nakamura Yoshisada, Sato Shingo, Itoh Isamu, Chem. Lett, 1988, 395-398.;3.33 g, 16 mmol) and sulfuric acid (conc, 14 ml) was added a mixture ofsulfuric acid (4 ml) and nitric acid (fuming, 2 ml) dropwise underice-water bath. The mixture was stirred at 55° C. for 1 h. The mixturewas poured onto ice-water and neutralized with 6N aqueous NaOH and thenextracted with dichloromethane. The organic layer was washed with brineand dried (Na2SO4). The solvent was removed under reduced pressure andthe residue was purified by flash chromatography eluting withhexane/ethyl acetate (2:1/1:1) to give 3 g (74%) of the title compoundas white solids.

[3239]¹H-NMR (CDCl₃) δ: 8.45 (1H, s), 7.65 (1H, s), 2.89 (3H, s).

[3240] Step 2. 1,5-dichloro-2-(methylsulfonyl)-4-nitrobenzene

[3241] A solution of 1,5-dichloro-2-(methylsulfinyl)-4-nitrobenzene (1.0g, 3.9 mmol) in dichloromethane (50 ml) was added 3-Chloroperoxybenzoicacid (1.7 g, 9.8 mmol). The mixture was stirred under nitrogen at roomtemperature for 3 h. The mixture was added saturated aqueous NaHCO₃ (20ml) and extracted with dichloromethane (50 ml). The organic layer waswashed with brine (50 ml), dried (Na₂SO₄) and concentrated. The residuewas purified by flash chromatography eluting with hexane/ethyl acetate(2:1) to give 1 g (100%) of the title compound as white solids.

[3242] MS (EI) m/z: 269 (M⁺).

[3243]¹H-NMR (CDCl₃) δ: 8.68 (1H, s), 7.81 (1H, s), 3.30 (3H, s).

[3244] Step 3.2-{4-[5-chloro-4-(methylsulfonyl)-2-nitroanilino]phenyl}ethanol

[3245] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from1,5-dichloro-2-(methylsulfonyl)-4-nitrobenzene and 4-aminophenylethylalcohol(step 2).

[3246] MS (EI) m/z: 370 (M⁺).

[3247]¹H-NMR (CDCl₃) δ: 9.81 (1H, br.s), 8.99 (1H, s), 7.39 (2H, d,J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.18 (1H, s), 3.94 (2H, t, J=6.2 Hz),3.25 (3H, s), 2.95 (2H, t, J=6.2 Hz).

[3248] Step 4.2-{4-[2-amino-5-chloro-4-(methylsulfonyl)anilino]phenyl}ethanol

[3249] The title compound was prepared according to the proceduredescribed in step 2 of Example 40 from2-{4-[5-chloro-4-(methylsulfonyl)-2-nitroanilino]phenyl}ethanol (step3).

[3250] MS (EI) m/z: 340(M⁺).

[3251]¹H-NMR (CDCl₃) δ: 7.50 (1H, s), 7.22 (2H, d, J=8.4 Hz), 7.15 (1H,s), 7.00 (2H, d, J=8.4 Hz), 5.71 (1H, br.s), 3.88 (2H, t, J=6.4 Hz),3.67 (2H, br.s), 3.22 (3H, s), 2.86 (2H, t, J=6.4 Hz).

[3252] Step 5.2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethylpropionate

[3253] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[2-amino-5-chloro-4-(methylsulfonyl)anilino]phenyl}ethanol (step4).

[3254] TLC, Rf=0.7, hexane:ethyl acetate (1:2).

[3255] Step 6.2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3256] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethylpropionate (step 5).

[3257] MS (EI) m/z: 378 (M⁺).

[3258]¹H-NMR (CDCl₃) δ: 8.60 (1H, s), 7.52 (2H, d, J=8.3 Hz), 7.28 (2H,d, J=8.3 Hz), 7.10 (1H, s), 3.97-4.04 (2H, m), 3.29 (3H, s), 3.03 (2H,t, J=6.5 Hz), 2.80 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).

[3259] Step 7.6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl methylsulfone

[3260] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 6).

[3261]¹H-NMR (CDCl₃) δ: 8.62 (1H, s), 7.50 (2H, d, J=8.4 Hz), 7.31 (2H,d, J=8.4 Hz), 7.24 (1H, s), 3.83 (2H, t, J=7.1 Hz), 3.29 (3H, s), 3.22(2H, t, J=7.1 Hz), 2.80 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).

[3262] Step 8.1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl methylsulfone

[3263] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl methylsulfone (step 7).

[3264]¹H-NMR (CDCl₃) δ: 8.62 (1H, s), 7.50 (2H, d, J=8.4 Hz), 7.25 (2H,d, J=8.4 Hz), 7.23 (1H, s), 3.64 (2H, t, J=6.9 Hz), 3.29 (3H, s), 3.04(2H, t, J=6.9 Hz), 2.80 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).

[3265] Step 9.2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethanamine

[3266] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-5-yl methylsulfone (step 8).

[3267]¹H-NMR (CDCl₃) δ: 8.61 (1H, s), 7.47 (2H, d, J=8.4 Hz), 7.28 (2H,d, J=8.4 Hz), 7.24 (1H, s), 3.29 (3H, s), 3.10 (2H, t, J=7.1 Hz), 2.90(2H, t, J=7.1 Hz), 2.80 (2H, q, J=7.5 Hz), 1.37 (3H, t, J=7.5 Hz).

[3268] Step 10.6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(methylsulfonyl)-1H-benzimidazole

[3269] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethanamine(step 9).

[3270] m.p.: 105-118° C.

[3271] IR (KBr) v: 2879, 1676, 1518, 1458, 1309, 1142, 1089, 993 cm⁻¹.

[3272] MS (ESI) m/z: 575 (MH⁺), 573 ([M−H]⁻).

[3273]¹H-NMR (CDCl₃) δ: 8.59 (1H, s), 7.75 (2H, d, J=8.4 Hz), 7.43 (2H,d, J=8.4 Hz), 7.29-7.33 (4H, m), 7.21 (1H, s), 6.69 (1H, br.s),3.55-3.62 (2H, m), 3.29 (3H, s), 2.96 (2H, t, J=6.9 Hz), 2.80 (3H, q,J=7.5 Hz), 2.41 (3H, s), 1.34 (3H, t, J=7.5 Hz).

Example 3246-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(methylsulfonyl)-1H-benzimidazolesodium salt

[3274] The title compound was prepared according to the proceduredescribed in Example 2 from6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(methylsulfonyl)-1H-benzimidazole(Example 323)

[3275] m.p.: 175-183° C.

[3276] IR (KBr) v: 3375, 1604, 1516, 1458, 1139, 1083, 993 cm⁻¹.

Example 3252-{4-[6-Chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyll}ethyl(4-mrthylphenyl)sulfonylcarbamate

[3277] Step 1.2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3278] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethanol(Example 323, step 6).

[3279] m.p.: 105-110° C.

[3280] IR (KBr) v: 1751, 1517, 1458, 1309, 1163, 1141, 1089 cm⁻¹.

[3281] MS (ESI) m/z: 576 (MH⁺), 574 ([M−H]⁻).

[3282]¹H-NMR (CDCl₃) δ: 8.60 (1H, s), 7.91-7.94 (2H, m), 7.21-7.43 (7H,m), 4.40 (2H, br.s), 3.31 (3H, s), 3.05 (2H, br.s), 2.78-2.81 (2H, m),2.44 (3H, s), 1.33 (3H, t, J=7.6 Hz).

Example 3265-(Aminosulfonyl)-6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[3283] Step 1. 2,4-dichloro-5-nitrobenzenesulfonyl chloride

[3284] 2,4-Dichloronitrobenzene (10 g, 52 mmol) was added ClSO3H (8 ml,120 mmol) dropwise under ice-water bath. The mixture was stirred at 130°C. for 26 h. The mixture was cooled to rt and poured onto ice-water. Theresulting precipitates were collected by filtration and dried underreduced pressure to give 9 g (60%) of the title compound as brownsolids.

[3285] MS (EI) m/z: 290 (M⁺).

[3286]¹H-NMR (CDCl₃) δ: 8.70 (1H, s), 7.90 (1H, s).

[3287] Step 2. N-(tert-butyl)-2,4-dichloro-5-nitrobenzenesulfonamide

[3288] The title compound was prepared according to the proceduredescribed in step 1 of Example 87 from2,4-dichloro-5-nitrobenzenesulfonyl chloride and tert-butylamine (step1).

[3289]¹H-NMR (CDCl₃) δ: 8.65 (1H, s), 7.74 (1H, s), 5.01 (1H, br.s),1.27 (9H, s).

[3290] Step 3.N-(tert-butyl)-2-chloro-4-[4-(2-hydroxyethyl)anilino]-5-nitrobenzenesulfonamide

[3291] The title compound was prepared according to the proceduredescribed in step 1 of Example 162 fromN-(tert-butyl)-2,4-dichloro-5-nitrobenzenesulfonamide and4-aminophenylethyl alcohol(step 2).

[3292]¹H-NMR (CDCl₃) δ: 9.72 (1H, br.s), 8.95 (1H, s), 7.37 (2H, d,J=8.3 Hz), 7.24 (2H, d, J=8.3 Hz), 7.17 (1H, s), 4.79 (1H, br.s),3.90-3.96 (2H, m), 2.94 (2H, t, J=6.4 Hz), 1.26 (9H, s).

[3293] Step 4.5-amino-N-(tert-butyl)-2-chloro-4-[4-(2-hydroxyethyl)anilino]benzenesulfonamide

[3294] The title compound was prepared according to the proceduredescribed in step 2 of Example 40 fromN-(tert-butyl)-2-chloro-4-[4-(2-hydroxyethyl)anilino]-5-nitrobenzenesulfonamide(step 3).

[3295] MS (EI) m/z: 397(M⁺).

[3296]¹H-NMR (CDCl₃) δ: 7.51 (1H, s), 7.20 (2H, d, J=8.4 Hz), 7.14 (1H,s), 6.95 (2H, d, J=8.4 Hz), 5.22 (1H, br.s), 4.89 (1H, br.s), 3.87 (2H,t, J=6.4 Hz), 2.85 (2H, t, J=6.4 Hz), 1.23 (9H, s).

[3297] Step 5.2-[4-(6-Chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[3298] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from5-amino-N-(tert-butyl)-2-chloro-4-[4-(2-hydroxyethyl)anilino]benzenesulfonamide(step 4).

[3299] TLC, Rf=0.8, hexane:ethyl acetate (1:2).

[3300] Step 6.N-(tert-butyl)-6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-sulfonamide

[3301] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(6-Chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]ethylpropionate (step 5).

[3302]¹H-NMR (CDCl₃) δ: 8.57 (1H, s), 7.49 (2H, d, J=8.4 Hz), 7.29 (2H,d, J=8.4 Hz), 7.20 (1H, s), 4.98 (1H, br.s), 4.00 (2H, br.s), 3.02 (2H,t, J=6.4 Hz), 2.79 (2H, q, J=7.5 Hz), 1.37 (3H, t, J=7.5 Hz), 1.21 (9H,s).

[3303] Step 7.N-(tert-butyl)-6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-sulfonamide

[3304] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 fromN-(tert-butyl)-6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-sulfonamide(step 6).

[3305]¹H-NMR (CDCl₃) δ: 8.58 (1H, s), 7.49 (2H, d, J=8.4 Hz), 7.32 (2H,d, J=8.4 Hz), 7.19 (1H, s), 4.96 (1H, br.s), 3.83 (2H, t, J=7.0 Hz),3.21 (2H, t, J=7.0 Hz), 2.80 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz),1.22 (9H, s).

[3306] Step 8.1-[4-(2-azidoethyl)phenyl]-N-(tert-butyl)-6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide

[3307] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 fromN-(tert-butyl)-6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-sulfonamide(step 7).

[3308]¹H-NMR (CDCl₃) δ:8.57 (1H, s), 7.48 (2H, d, J=8.2 Hz), 7.32 (2H,d, J=8.2 Hz), 7.19 (1H, s), 4.96 (1H, br.s), 3.63 (2H, t, J=6.9 Hz),3.03 (2H, t, J=6.9 Hz), 2.79 (2H, q, J=7.4 Hz), 1.37 (3H, t, J=7.4 Hz),1.21 (9H, s).

[3309] Step 9.1-[4-(2-aminoethyl)phenyl]-N-(tert-butyl)-6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide

[3310] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-N-(tert-butyl)-6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide(step 8).

[3311]¹H-NMR (CDCl₃) δ: 8.57 (1H, s), 7.44 (2H, d, J=8.5 Hz), 7.29 (2H,d, J=8.5 Hz), 7.20 (1H, s), 5.03 (1H, br.s), 3.09 (2H, t, J=6.9 Hz),2.89 (2H, t, J=6.9 Hz), 2.79 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz),1.22 (9H, s).

[3312] Step 10.5-[(tert-butylamino)sulfonyl]-6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[3313] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-[4-(2-aminoethyl)phenyl]-N-(tert-butyl)-6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide(step 9).

[3314]¹H-NMR (CDCl₃) δ: 8.54 (1H, s), 7.78 (2H, d, J=8.3 Hz), 7.41 (2H,d, J=8.3 Hz), 7.31 (2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.2 Hz), 7.16 (1H,s), 6.61 (1H, br.s), 5.21 (1H, br.s), 3.54-3.60 (2H, m), 2.95 (2H, t,J=6.9 Hz), 2.78 (2H, q, J=7.5 Hz), 2.41 (3H, s), 1.35 (3H, t, J=7.5 Hz),1.21 (9H, s).

[3315] Step 11.5-(aminosulfonyl)-6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

[3316] The title compound was prepared according to the proceduredescribed in step 1 of Example 88 from5-[(tert-butylamino)sulfonyl]-6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole(step 9).

[3317] m.p.: 163-170° C.

[3318] IR (KBr) v: 1676, 1517, 1400, 1340, 1159, 1089, 995 cm⁻¹.

[3319] MS (ESI) m/z: 576 (MH⁺), 574 ([M−H]⁻).

[3320]¹H-NMR (DMSO-d₆) δ: 8.25 (1H, s), 7.77 (2H, d, J=8.3 Hz), 7.55(2H, br.s), 7.37-7.48 (6H, m), 7.20 (1H, s), 6.54 (1H, br.s), 3.27 (2H,br.s), 2.71-2.81 (4H, m), 2.34 (3H, s), 1.23 (3H, t, J=7.6 Hz).

Example 3272-{4-[5-(Aminosulfonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3321] Step 1.2-(4-{5-[(tert-butylamino)sulfonyl]-6-chloro-2-ethyl-1H-benzimidazol-1-yl}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate

[3322] The title compound was prepared according to the proceduredescribed in Example 3 fromN-(tert-butyl)-6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-sulfonamide(Example 326, step 6).

[3323]¹H-NMR (CDCl₃) δ: 8.58 (1H, s), 7.93 (2H, d, J=8.2 Hz), 7.33-7.39(4H, m), 7.20 (2H, d, J=˜8.2 Hz), 7.16 (1H, s), 5.07 (1H, br.s), 4.38(2H, t, J=6.2 Hz), 3.03 (2H, t, J=6.2 Hz), 2.78 (2H, q, J=7.5 Hz), 2.44(3H, s), 1.35 (3H, t, J=7.5 Hz), 1.21 (9H, s).

[3324] Step 2.2-{4-[5-(aminosulfonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3325] The title compound was prepared according to the proceduredescribed in step 1 of Example 88 from2-(4-{5-[(tert-butylamino)sulfonyl]-6-chloro-2-ethyl-1H-benzimidazol-1-yl}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate (step 1).

[3326] m.p.: 110-115° C.

[3327] IR (KBr) v: 1676, 1517, 1400, 1340, 1159, 1089, 995 cm⁻¹.

[3328] MS (ESI) m/z: 576 (MH⁺), 574 ([M−H]⁻).

[3329]¹H-NMR (DMSO-d₆) δ: 8.25 (1H, s), 7.76 (2H, d, J=8.4 Hz), 7.55(2H, br.s), 7.47 (4H, s), 7.41 (2H, d, J=8.4 Hz), 7.20 (1H, s), 4.29(2H, t, L=6.6 Hz), 2.96 (2H, t, J=6.6 Hz), 2.75 (2H, q, J=7.5 Hz), 2.35(3H, s), 1.24 (3H, t, J=7.5 Hz).

Example 3282-[4-(6-Chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3330] Step 1.2-[4-(6-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3331] The title compound was prepared according to the proceduredescribed in Example 3 from6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile(Example 111, step 4).

[3332] m.p.: 85-98° C.

[3333] IR (KBr) v: 1747, 1618, 1517, 1465, 1348, 1290, 1163, 1089 cm⁻¹.

[3334] MS (ESI) m/z: 523 (MH⁺), 521 ([M−H]⁻).

[3335]¹H-NMR (CDCl₃) δ: 8.07 (1H, s), 7.92 (2H, d, J=8.4 Hz), 7.40 (2H,d, J=8.4 Hz), 7.35 (2H, d, J=8.1 Hz), 7.25 (2H, d, J=8.1 Hz), 7.17 (1H,s), 4.39 (2H, t, J=6.8 Hz), 3.04 (2H, t, J=6.8 Hz), 2.78 (2H, q, J=7.6Hz), 2.44 (3H, s), 1.35 (3H, t, J=7.6 Hz).

Example 329N-[({2-[4-(5-Cyano-2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl]-4-methyklbenzenesulfonamide

[3336] Step 1. 4-cyano-3,5-dimethyl-2-nitrophenyltrifluoromethanesulfonate

[3337] To a solution of 4-hydroxy-2,6-dimethyl-3-nitro-benzonitrile(v.Auwers; Saurwein; Fortsch. Ch. Phys.; 18; Heft 2, S. 23; 2.6 g, 13.4mmol) in dichloromethane (150 ml) was added triflic anhydride (3.4 ml,20 mmol) and pyridine (1.5 ml, 20 mmol) at 0° C. The mixture was stirredat room temperature for 1.5 h. The reaction mixture was poured intowater, and extracted with ethyl acetate (100 ml). The organic layer waswashed with brine (50 ml), then dried (Na2SO₄). After removal ofsolvent, the crude product was purified by flash column chromatographyeluting with hexane/ethyl acetate (2:1) to afford 3 g (69%) of the titlecompound as pale yellow solids.

[3338] MS (EI) m/z: 324 (M+).

[3339]¹H-NMR (CDCl₃) δ: 7.34 (1H, s), 2.68 (3H, s), 2.61 (3H, s).

[3340] Step 2.2-{4-[(4-cyano-3,5-dimethyl-2-nitrophenyl)amino]phenyl}ethyl acetate

[3341] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from 4-cyano-3,5-dimethyl-2-nitrophenyltrifluoromethanesulfonate (step 1).

[3342]¹H-NMR (CDCl₃) δ: 8.08 (1H, br.s), 7.27 (2H, d, J=8.4 Hz), 7.15(2H, d, J=8.4 Hz), 4.30 (2H, t, J=7.0 Hz), 2.96 (2H, t, J=7.0 Hz), 2.65(3H, s), 2.41 (3H, s), 2.05 (3H, s).

[3343] Step 3.2-{4-[(4-cyano-3,5-dimethyl-2-nitrophenyl)amino]phenyl}ethyl acetate

[3344] The title compound was prepared according to the proceduredescribed in step 3 of Example 6 from2-{4-[(4-cyano-3,5-dimethyl-2-nitrophenyl)amino]phenyl}ethyl acetate(step 2).

[3345]¹H-NMR (CDCl₃) δ: 7.14 (2H, d, J=8.4 Hz), 6.85-6.89 (3H, m), 5.50(1H, br.s), 4.26 (2H, t, J=7.1 Hz), 3.54 (2H, br.s), 2.89 (2H, t, J=7.1Hz), 2.41 (3H, s), 2.37 (3H, s), 2.05 (3H, s).

[3346] Step 4.2-[4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethylacetate

[3347] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(4-cyano-3,5-dimethyl-2-nitrophenyl)amino]phenyl}ethyl acetate(step 3).

[3348]¹H-NMR (CDCl₃) δ: 7.45-7.47 (2H, m), 7.26-7.29 (2H, m), 6.79 (1H,br.s), 4.37 (2H, t, J=7.0 Hz), 3.08 (2H, t, J=7.0 Hz), 2.83-2.89 (5H,m), 2.56 (3H, s), 2.09 (3H, s), 1.28 (3H, br.s).

[3349] Step 5.2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-4,6-dimethyl-1H-benzimidazole-5-carbonitrile

[3350] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethylacetate (step 4).

[3351] MS (EI) m/z: 319 (M+).

[3352]¹H-NMR (CDCl₃) δ: 7.40-7.51 (4H, m), 6.93 (1H, s), 3.68-3.75 (2H,m), 2.85 (2H, t, J=6.7 Hz), 2.68-2.76 (5H, m), 2.50 (3H, s), 1.22 (3H,t, J=7.4 Hz).

[3353] Step 6.1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile

[3354] The title compound was prepared according to the proceduredescribed in step 7 Example 1 from2-ethyl-1-[4-(2-hydroxyethyl)phenyl]4,6-dimethyl-1H-benzimidazole-5-carbonitrile(step 5).

[3355]¹H-NMR (CDCl₃) δ: 7.45 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz),6.79 (1H, s), 3.83 (2H, t, J=7.1 Hz), 3.21 (2H, t, J=7.1 Hz), 2.88 (3H,s), 2.81 (2H, q, J=7.6 Hz), 2.55 (3H, s), 1.29 (3H, t, J=7.6 Hz).

[3356] Step 7.1-[4-(2-azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile

[3357] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile(step 6).

[3358] MS (EI) m/z: 412 (M+).

[3359]¹H-NMR (CDCl₃) δ: 7.47 (2H, d, J=8.1 Hz), 7.28 (2H, d, J=8.1 Hz),6.78 (1H, s), 3.63 (2H, t, J=6.8 Hz), 3.03 (2H, t, J=6.8 Hz), 2.87 (3H,s), 2.80 (2H, q, J=7.6 Hz), 2.55 (3H, s), 1.29 (3H, t, J=7.6 Hz).

[3360] Step 8.1-[4-(2-aminoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile

[3361] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile(step 7).

[3362]¹H-NMR (CDCl₃) δ: 7.43 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz),6.79 (1H, s), 3.08 (2H, t, J=7.0 Hz), 2.63-2.91 (7H, m), 2.55 (3H, s),1.29 (3H, t, J=7.6 Hz).

[3363] Step 9.N-[({2-[4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

[3364] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-[4-(2-aminoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile(step 8).

[3365] m.p.: 140-145° C.

[3366] IR (KBr) v: 3340, 2214, 1664, 1517, 1338, 1166, 1091 cm⁻¹.

[3367] MS (ESI) m/z: 516 (MH⁺), 514 ([M−H]⁻).

[3368]¹H-NMR (CDCl₃) δ: 7.71 (2H, d, J=8.4 Hz), 7.41 (2H, d, J=8.4 Hz),7.25-7.31 (4H, m), 6.77 (1H, s), 6.73 (1H, br.s), 3.55-3.62 (2H, m),2.95 (2H, t, J=7.0 Hz), 2.87 (3H, s), 2.80 (2H, q, J=7.6 Hz), 2.52 (3H,s), 2.41 (3H, s), 1.28 (3H, t, J=7.6 Hz).

Example 3302-{4-[5-(Aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3369] Step 1.2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3370] The title compound was prepared according to the proceduredescribed in Example 3 from6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide(Example 111, step 5)

[3371] m.p.: 170-175° C.

[3372] IR (KBr) v: 3463, 3342, 1747, 1685, 1593, 1161, 1080, 881 cm⁻¹.

[3373] MS (ESI) m/z: 541 (MH⁺), 539 ([M−H]⁻).

[3374]¹H-NMR (CDCl₃) δ: 8.13 (1H, s), 7.96 (2H, d, J=8.4 Hz), 7.40 (2H,d, J=8.4 Hz), 7.36 (2H, d, J=8.1 Hz), 7.01 (2H, d, J=8.1 Hz), 6.94 (1H,s), 6.55 (1H, br.s), 4.38 (2H, t, J=6.1 Hz), 3.01 (2H, t, J=6.1 Hz),2.70 (2H, q, J=7.5 Hz), 2.45 (3H, s), 1.29 (3H, t, J=7.5 Hz).

Example 3312-[4-(5-Cyano-2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3375] Step 1.2-[4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3376] The title compound was prepared according to the proceduredescribed in Example 3 from2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-4,6-dimethyl-1H-benzimidazole-5-carbonitrile(Example 329, step 5)

[3377] m.p.: 208-213° C.

[3378] IR (KBr)v: 1747, 1517, 1230, 1161, 1089 cm⁻¹.

[3379] MS (ESI) m/z: 517 (MH⁺), 515 ([M−H]⁻).

[3380]¹H-NMR (DMSO-d₆) δ: 7.76 (2H, d, J=8.4 Hz), 7.40-7.48 (6H, m),6.91 (1H, s), 4.27 (2H, t, J=6.7 Hz), 2.96 (2H, t, J=6.7 Hz), 2.67-2.73(5H, m), 2.48 (3H, s), 2.36 (3H, s), 1.21 (3H, t, J=7.6 Hz).

Example 332 2-[4-(5-Acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3381] Step 1. 2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3382] The title compound was prepared according to the proceduredescribed in Example 3 from1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}ethanone(Example 78, step 4)

[3383] m.p.: 188-190° C.

[3384] IR (KBr) v: 1743, 1683, 1606, 1515, 1348, 1163, 1076 cm⁻¹.

[3385] MS (ESI) m/z: 506 (MH⁺), 504 ([M−H]⁻).

[3386]¹H-NMR (DMSO-d₆) δ: 8.33 (1H, d, J=1.4 Hz), 7.82 (1H, dd, J=1.4Hz, 8.4 Hz), 7.76 (2H, d, J=8.4 Hz), 7.45 (4H, s), 7.40 (2H, d, J=8.4Hz), 7.14 (1H, d, J=8.4 Hz), 4.28 (2H, t, J=6.5 Hz), 2.97 (2H, t, J=6.5Hz), 2.75 (2H, q, J=7.4 Hz), 2.64 (3H, s), 2.35 (3H, s), 1.25 (3H, t,J=7.4 Hz).

Example 3336-Chloro-2-ethyl-N-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

[3387] Step 1. 2,4-dichloro-N-methyl-5-nitrobenzamide

[3388] To a solution of 2,4-dichloro-5-nitrobenzoic acid (8 g, 33.9mmol) in toluene (200 ml) was added thionyl chloride (12.4 ml, 169 mmol)at room temperature. The mixture was stirred at 80° C. for 5 h. Thesolvent was removed and the residue was dissolved with tetrahydrofurane(60 ml). The mixture was added 40% methylamine (1.4 ml, 33.9 mmol) at 0°C. and the mixture was stirred at room temperature for 2.5 h. Thevolatile component was removed under reduced pressure, and the residuewas extracted with ethyl acetate (100 ml). The organic layer was washedwith water (100 ml), brine (100 ml), then dried (Na₂SO₄). After removalof solvent, the crude product was purified by flash columnchromatography eluting with hexane/ethyl acetate (2:1/1:1/1:2) to afford5.3 g (63%) of the title compound as pale yellow solids.

[3389]¹H-NMR (CDCl₃) δ: 8.27 (1H, s), 7.65 (1H, s), 3.15 (3H, s).

[3390] Step 2.2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N-methyl-5-nitrobenzamide

[3391] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from2,4-dichloro-N-methyl-5-nitrobenzamide (step 1).

[3392]¹H-NMR (CDCl₃) δ: 9.62 (1H, s), 8.22 (1H, s), 7.24-7.35 (4H, m),6.95 (1H, s), 3.60-3.67 (2H, m), 2.73-2.79 (5H, m).

[3393] Step 3.5-amino-2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N-methylbenzamide

[3394] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N-methyl-5-nitrobenzamide(step 2).

[3395]¹H-NMR (CDCl₃) δ: 7.28 (1H, s), 7.15 (2H, d, J=8.4 Hz), 7.08 (1H,s), 6.89 (2H, d, J=8.4 Hz), 6.53 (1H, br.s), 5.41 (1H, br.s), 3.84-3.86(2H, m), 3.66 (2H, br.s), 3.00 (3H, d, J=5.0 Hz), 2.83 (2H, t, J=6.6Hz).

[3396] Step 4.6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-N-methyl-1H-benzimidazole-5-carboxamide

[3397] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from5-amino-2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N-methylbenzamide(step 3).

[3398] MS (EI) m/z: 357 (M+).

[3399]¹H-NMR (CDCl₃) δ: 7.98 (1H, s), 7.47 (2H, d, J=8.1 Hz), 7.27 (2H,d, J=8.1 Hz), 7.09 (1H, s), 6.23 (1H, br.s), 3.96-4.02 (2H, m), 3.05(3H, d, J=4.9 Hz), 3.00 (2H, t, J=6.4 Hz), 2.77 (2H, q, J=7.6 Hz), 1.34(3H, t, J=7.6 Hz).

[3400] Step 5.6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide

[3401] The title compound was prepared according to the proceduredescribed in step 7 Example 1 from6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-N-methyl-1H-benzimidazole-5-carboxamide(step 4).

[3402]¹H-NMR (CDCl₃) δ: 7.98 (1H, s), 7.47 (2H, d, J=8.3 Hz), 7.31 (2H,d, J=8.3 Hz), 7.10 (1H, s), 6.35 (1H, br.s), 3.83 (2H, t, J=6.9 Hz),3.21 (2H, t, J=6.9 Hz), 3.05 (3H, d, J=4.9 Hz), 2.82 (2H, q, J=7.6 Hz),1.36 (3H, t, J=7.6 Hz).

[3403] Step 6.1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide

[3404] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide(step 5).

[3405] MS (EI) m/z: 382 (M+).

[3406]¹H-NMR (CDCl₃) δ: 7.94 (1H, s), 7.46 (2H, d, J=8.0 Hz), 7.27 (2H,d, J=8.0 Hz), 7.06 (1H, s), 3.63 (2H, t, J=7.0 Hz), 2.98-3.06 (5H, m),2.77 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.6 Hz).

[3407] Step 7.1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide

[3408] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide(step 6).

[3409]¹H-NMR (CDCl₃) δ: 7.91 (1H, s), 7.42 (2H, d, J=8.4 Hz), 7.24 (2H,d, J=8.4 Hz), 7.06 (1H, s), 6.55 (1H, br.s), 3.03-3.10 (5H, m),2.72-2.83 (2H, m), 1.33 (3H, t, J=7.6 Hz).

[3410] Step 8.6-chloro-2-ethyl-N-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

[3411] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide(step 7).

[3412] m.p.: 122-135° C.

[3413] IR (KBr) v: 2877, 1637, 1519, 1400, 1340, 1161, 1091 cm⁻¹.

[3414] MS (ESI) m/z: 554 (MH⁺), 552 ([M−H]⁻).

[3415]¹H-NMR (CDCl₃) δ: 7.79-7.84 (3H, m), 7.28-7.33 (4H, m), 7.12 (2H,d, J=8.2 Hz), 6.96 (1H, s), 6.80 (1H, br.s), 6.70 (1H, br.s), 3.48-3.54(2H, m), 3.08 (3H, d, J=4.8 Hz), 2.89 (2H, t, J=6.9 Hz), 2.72 (2H, q,J=7.5 Hz), 2.41 (3H, s), 1.30 (3H, t, J=7.5 Hz).

Example 3342-(4-{6Chloro-2-ethyl-5-[(methylamino)carbonyl-1H-benzimidazol-1-yl}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate

[3416] Step 1.2-(4-{6-chloro-2-ethyl-5-[(methylamino)carbonyl]-1H-benzimidazol-1-yl}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate

[3417] The title compound was prepared according to the proceduredescribed in Example 3 from6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-N-methyl-1H-benzimidazole-5-carboxamide(Example 333, step 4).

[3418] m.p.: 201-204° C.

[3419] MS (ESI) m/z: 555 (MH⁺), 553 ([M−H]⁻).

[3420]¹H-NMR (DMSO-d₆) δ: 8.27-8.29 (1H, m), 7.76 (2H, d, J=8.1 Hz),7.69 (1H, s), 7.40-7.48 (6H, m), 7.06 (1H, s), 4.28 (2H, t, J=6.3 Hz),2.96 (2H, t, J=6.3 Hz), 2.69-2.78 (5H, m), 2.36 (3H, s), 1.23 (3H, t,J=7.5 Hz).

Example 3352-{4-[6Chloro-5-[(dimethylamino)carbonyl]-2-(1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3421] Step 1. 2,4-dichloro-N,N-dimethyl-5-nitrobenzamide

[3422] To a solution of 2,4-dichloro-5-nitrobenzoic acid (4 g, 17 mmol)in toluene (50 ml) was added thionyl chloride (6 ml, 84 mmol) at roomtemperature. The mixture was stirred at 80° C. for 2 days. The solventwas removed and the residue was dissolved with tetrahydrofurane (30 ml).The mixture was added 50% dimethylamine (760 mg) at 0° C. and themixture was stirred at room temperature over night. The volatilecomponent was removed under reduced pressure, and the residue wasextracted with ethyl acetate (100 ml). The organic layer was washed withwater (50 ml), brine (50 ml), then dried (Na₂SO₄). After removal ofsolvent, the crude product was purified by flash column chromatographyeluting with hexane/ethyl acetate (1:1) to afford 3.6 g (82%) of thetitle compound as pale yellow solids.

[3423]¹H-NMR (CDCl₃) δ: 7.90 (1H, s), 7.65 (1H, s), 3.15 (3H, s), 2.91(3H, s).

[3424] Step 2.2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N,N-dimethyl-5-nitrobenzamide

[3425] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from2,4-dichloro-N,N-dimethyl-5-nitrobenzamide (step 1).

[3426] MS (EI) m/z: 363 (M+).

[3427]¹H-NMR (CDCl₃) δ: 9.52 (1H, br.s), 8.20 (1H, s), 7.34 (2H, d,J=8.2 Hz), 7.22 (2H, d, J=8.2 Hz), 7.16 (1H, s), 3.92 (2H, m), 3.13 (3H,s), 2.89-2.94 (5H, m).

[3428] Step 3.5-amino-2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N,N-dimethylbenzamide

[3429] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N,N-dimethyl-5-nitrobenzamide(step 2).

[3430]¹H-NMR (CDCl₃) δ: 7.05-7.11 (3H, m), 6.79 (2H, d, J=8.5 Hz), 6.63(1H, s), 5.59 (1H, s), 3.79-3.83 (4H, m), 3.11 (3H, s), 2.92 (3H, s),2.79 (2H, t, J=6.4 Hz).

[3431] Step 4.2-{4-[6-chloro-5-[(dimethylamino)carbonyl]-2-(1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethylpropanoate

[3432] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from5-amino-2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N,N-dimethylbenzamide(step 3).

[3433] Step 5.6-chloro-1-[4-(2-hydroxyethyl)phenyl]-N,N-dimethyl-2-(1-methylethyl)-1H-benzimidazole-5-carboxamide

[3434] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[6-chloro-5-[(dimethylamino)carbonyl]-2-(1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethylpropanoate (step 4).

[3435] MS (EI) m/z: 371 (M+).

[3436]¹H-NMR (CDCl₃) δ: 7.66 (1H, s), 7.46 (2H, d, J=8.5 Hz), 7.27 (2H,d, J=8.5 Hz), 7.12 (1H, s), 3.95-4.00 (2H, m), 3.17 (3H, s), 3.00 (2H,d, J=6.6 Hz), 2.87 (3H, s), 2.78 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5Hz).

[3437] Step 6.2-{4-[6-chloro-5-[(dimethylamino)carbonyl]-2-(1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3438] The title compound was prepared according to the proceduredescribed in Example 3 from6-chloro-1-[4-(2-hydroxyethyl)phenyl]-N,N-dimethyl-2-(1-methylethyl)-1H-benzimidazole-5-carboxamide(step 5).

[3439] m.p.: 173-176° C.

[3440] IR (KBr) v: 1741, 1637, 1519, 1398, 1344, 1159, 1078, 904 cm⁻¹.

[3441] MS (ESI) m/z: 569 (MH⁺), 567 ([M−H]⁻).

[3442]¹H-NMR (CDCl₃) δ: 7.93 (2H, d, J=8.4 Hz), 7.70 (1H, s), 7.27-7.34(4H, m), 7.09-7.12 (3H, m), 4.35 (2H, t, J=6.6 Hz), 3.19 (3H, s), 2.98(2H, t, J=6.6 Hz), 2.88 (3H, s), 2.74 (2H, q, J=7.5 Hz), 2.42 (3H, s),1.29 (3H, t, J=7.5 Hz).

Example 3362-(4-{6-Chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazol-1-yl}phenyl)ethyl(4-methylphenyl)suklfonylcarbamate

[3443] Step 1. 1,5-dichloro-2-[(methyloxy)methyl]-4-nitrobenzene

[3444] To a solution of 1,5-dichloro-2-(chloromethyl)-4-nitrobenzene(Hagmann, William K.; Dorn, Conrad P.; Frankshun, Robert A.; O'Grady,Laura A.; Bailey, Philip J.; et al.; JMCMAR; J.Med.Chem.; EN; 29; 8;1986; 1436-1441, 10.6 g, 44 mmol) in methanol (30 ml) was added sodiummethoxide (44 ml, 66 mmol) at room temperature. The mixture was stirredat 80° C. for 21 h. The volatile component was removed under reducedpressure, and the residue was extracted with ethyl acetate (100 ml). Theorganic layer was washed with water (50 ml), brine (50 ml), then dried(Na₂SO₄). After removal of solvent, the crude product was purified byflash column chromatography eluting with hexane/ethyl acetate (6:1/4:1)to afford 2.8 g (27%) of the title compound as pale yellow oil.

[3445]¹H-NMR (CDCl₃) δ: 8.01 (1H, s), 7.09 (1H, s), 4.49 (2H, s), 3.96(3H, s).

[3446] Step 2.2-[4-({5-chloro-4-[(methyloxy)methyl]-2-nitrophenyl}amino)phenyl]ethanol

[3447] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from1,5-dichloro-2-[(methyloxy)methyl]-4-nitrobenzene (step 1).

[3448]¹H-NMR (CDCl₃) δ: 9.45 (1H, br.s), 8.28 (1H, s), 7.17-7.33 (5H,m), 4.44 (2H, s), 3.91 (1H, br.s), 3.45 (3H, s), 2.91 (2H, t, J=6.6 Hz).

[3449] Step 3.2-[4-({2-amino-5-chloro-4-[(methyloxy)methyl]phenyl}amino)phenyl]ethanol

[3450] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-[4-({5-chloro-4-[(methyloxy)methyl]-2-nitrophenyl}amino)phenyl]ethanol(step 2).

[3451]¹H-NMR (CDCl₃) δ: 7.07-7.01 (3H, m), 6.88 (1H, s), 6.74 (2H, d,J=8.4 Hz), 5.16 (1H, br.s), 4.47 (2H, s), 3.82 (2H, t, J=6.6 Hz), 3.71(2H, br.s), 3.46 (3H, s), 2.79 (2H, t, J=6.6 Hz).

[3452] Step 4.2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazol-1-yl}phenyl)ethanol

[3453] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-({2-amino-5-chloro-4-[(methyloxy)methyl]phenyl}amino)phenyl]ethanol(step 3).

[3454] MS (EI) m/z: 344 (M+).

[3455]¹H-NMR (CDCl₃) δ: 7.82 (1H, s), 7.46 (2H, d, J=8.2 Hz), 7.28 (2H,d, J=8.2 Hz), 7.12 (1H, s), 4.65 (1H, s), 3.99 (2H, br.s), 3.45 (3H, s),3.00 (3H, t, J=7.6 Hz), 2.78 (2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz).

[3456] Step 5.2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazol-1-yl}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate

[3457] The title compound was prepared according to the proceduredescribed in Example 3 from2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazol-1-yl}phenyl)ethanol(step 4).

[3458] m.p.: 174.5° C.

[3459] IR (KBr) v: 3377, 2813, 1718, 1519, 1398, 1342, 1159, 1093, 1062cm⁻¹.

[3460] MS (ESI) m/z: 542 (MH⁺), 540 ([M−H]⁻).

[3461]¹H-NMR (CDCl₃) δ: 7.94 (2H, d, J=8.2 Hz), 7.83 (1H, s), 7.08-7.33(7H, m), 4.64 (s, 2H), 4.37 (2H, t, J=6.4 Hz), 3.46 (3H, s), 2.97 (2H,t, J=6.4 Hz), 2.73 (2H, q, J=7.5 Hz), 2.42 (3H, s), 1.26 (3H, t, J=7.5Hz).

Example 3372-{4-[6-Chloro-2-ethyl-5-(hydroxymethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3462] Step 1.2-{4-[6-chloro-5-(chloromethyl)-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethanol

[3463] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-[4-({2-amino-5-chloro-4-[(methyloxy)methyl]phenyl}amino)phenyl]ethanol(Example 336, step 3).

[3464] MS (EI) m/z: 348 (M+).

[3465]¹H-NMR (CDCl₃) δ: 7.83 (1H, s), 7.46 (2H, d, J=8.2 Hz), 7.27 (2H,d, J=8.2 Hz), 7.15 (1H, s), 4.84 (2H, s), 3.96-4.02 (2H, m), 3.00 (2H,t, J=6.4 Hz), 2.77 (2H, q, J=7.5 Hz), 1.34 (2H, t, J=7.5 Hz).

[3466] Step 2.6-chloro-5-(chloromethyl)-1-[4-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazole

[3467] The title compound was prepared according to the proceduredescribed in step 2 of Example 90 from2-{4-[6-chloro-5-(chloromethyl)-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethanol(step 1).

[3468] MS (EI) m/z: 405 (M+).

[3469]¹H-NMR (CDCl₃) δ: 7.83 (1H, s), 7.43 (2H, d, J=8.4 Hz), 7.23 (2H,d, J=8.4 Hz), 7.11 (1H, s), 4.85 (2H, s), 3.91 (2H, t, J=6.4 Hz), 2.94(2H, t, J=6.4 Hz), 2.76 (2H, q, J=7.5 Hz), 1.33 (3H, t, J=7.5 Hz), 0.87(9H, s), 0.00 (6H, s).

[3470] Step 3.{6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}methylpropanoate

[3471] To a solution of6-chloro-5-(chloromethyl)-1-[4-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazole(step 2, 403 mg, 0.86 mmol) in N,N-dimethylformamide (10 ml) was addedpropionic acid (0.06 ml, 0.86 mmol) and NaHCO₃ (144 mg, 1.72 mmol) atroom temperature. The mixture was stirred at 60° C. for 7 h. The mixturewas added water (50 ml) and extracted with ethyl acetate(100 ml). Theorganic layer was washed with brine (50 ml), then dried (Na₂SO₄). Afterremoval of solvent, the crude product was purified by flash columnchromatography eluting with hexane/ethyl acetate (8:1/4:1) to afford 235mg (53%) of the title compound as pale yellow oil.

[3472]¹H-NMR (CDCl₃) δ: 7.81 (1H, s), 7.43 (2H, d, J=8.5 Hz), 7.24 (2H,d, J=8.5 Hz), 7.11 (1H, s), 5.33 (2H, s), 3.91 (2H, t, J=6.6 Hz), 2.93(2H, t, J=6.6 Hz), 2.77 (2H, q, J=7.5 Hz), 2.42 (2H, q, J=7.5 Hz), 1.33(3H, t, J=7.5 Hz), 1.18 (3H, t, J=7.5 Hz), 0.87 (9H, s), 0.00 (6H, s).

[3473] Step 4.{6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}methylpropanoate

[3474] The title compound was prepared according to the proceduredescribed in step 6 of Example 90 from{6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}methylpropanoate (step 3).

[3475] MS (EI) m/z: 386 (M+).

[3476]¹H-NMR (CDCl₃) δ: 7.70 (1H, s), 7.37 (2H, d, J=8.3 Hz), 7.17 (2H,d, J=8.3 Hz), 7.04 (1H, s), 5.21 (2H, s), 3.88 (2H, d, J=6.6 Hz), 2.91(2H, t, J=6.6 Hz), 2.67 (2H, q, J=7.5 Hz), 2.32 (2H, q, J=7.5 Hz), 1.24(3H, t, J=7.5 Hz), 1.08 (3H, t, J=7.5 Hz).

[3477] Step 5.[6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenyl)-1H-benzimidazol-5-yl]methylpropanoate

[3478] The title compound was prepared according to the proceduredescribed in Example 3 from{6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimnidazol-5-yl}methylpropanoate (step 4).

[3479]¹H-NMR (CDCl₃) δ: 7.92 (2H, d, J=8.3 Hz), 7.81 (1H, s), 7.32-7.36(4H, m), 7.21-7.25 (2H, m), 7.10 (1H, s), 5.32 (2H, s), 4.38 (2H, t,J=6.7 Hz), 3.02 (2H, t, J=6.7 Hz), 2.76 (2H, q, J=7.6 Hz), 2.37-2.49(5H, m), 1.33 (3H, t, J=7.6 Hz), 1.18 (3H, t, J=7.6 Hz).

[3480] Step 6.2-{4-[6-chloro-2-ethyl-5-(hydroxymethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3481] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from[6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenyl)-1H-benzimidazol-5-yl]methylpropanoate (step 5).

[3482] m.p.: 172.7° C.

[3483] IR (KBr) v: 1745, 1519, 1240, 1160, 1089, 1058 cm⁻¹.

[3484] MS (ESI) m/z: 528 (MH⁺), 526 ([M−H]⁻).

[3485]¹H-NMR (DMSO-d₆) δ: 7.74-7.77 (3H, m), 7.39-7.46 (6H, m), 7.03(1H, s), 4.63 (2H, s), 4.27 (2H, t, J=6.6 Hz), 2.95 (2H, t, J=6.6 Hz),2.72 (2H, q, J=7.5 Hz), 2.34 (3H, s), 1.23 (3H, t, J=7.5 Hz).

Example 338N-({[2-(4-{6-Chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazol-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzensulfonamide

[3486] Step 1.1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazole

[3487] The title compound was prepared according to the proceduredescribed in step 5 of Example 26 from2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazol-1-yl}phenyl)ethanol(Example 336, step 4).

[3488] MS (EI) m/z: 369 (M⁺).

[3489]¹H-NMR (CDCl₃) δ: 7.82 (1H, s), 7.45 (2H, d, J=8.4 Hz), 7.30 (2H,d, J=8.4 Hz), 7.11 (1H, s), 4.65 (2H, s), 3.62 (2H, t, J=7.0 Hz), 3.45(3H, s), 3.02 (2H, t, J=J=7.0 Hz), 2.77 (2H, q, J=7.7 Hz), 1.34 (3H, t,J=7.7 Hz).

[3490] Step 2.2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazol-1-yl}phenyl)ethanamine

[3491] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazole(step 1).

[3492]¹H-NMR (CDCl₃) δ: 7.82 (1H, s), 7.42 (2H, d, J=8.4 Hz), 7.24-7.29(2H, m), 7.12 (1H, s), 4.65 (1H, s), 3.45 (3H, ds), 3.08 (2H, t, J=6.7Hz), 2.88 (2H, t, J=6.7 Hz), 2.77 (2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6Hz).

[3493] Step 3.N-({[2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazol-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide

[3494] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazol-1-yl}phenyl)ethanamine(step 2).

[3495] m.p.: 134.6° C.

[3496] IR (KBr) v: 3377, 2813, 1718, 1519, 1398, 1342, 1159, 1093, 1062cm⁻¹.

[3497] MS (ESI) m/z: 541 (MH⁺), 539 ([M−H]⁻).

[3498]¹H-NMR (CDCl₃) δ: 7.82 (1H, s), 7.72 (2H, d, J=8.4 Hz), 7.24-7.39(4H, m), 7.09 (1H, s), 6.72 (1H, br.s), 4.65 (2H, s), 3.57 (2H, m), 3.45(3H, s), 2.93 (2H, d, J=6.8 Hz), 2.77 (2H, q, J=7.5 Hz), 2.40 (3H, s),1.32 (3H, t, J=7.5 Hz).

Example 3392-{4-[6-Chloro-2-[3-(4pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3499] Step 1.2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate

[3500] To a mixture of2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol(Example 104, step 1, 8.1 g, 22.4 mmol) and pyridine (1.8 ml, 22.45mmol) in dichloromethane (200 ml) was added acetyl chloride (1.6 ml,22.4 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min. Themixture was added water (50 ml) and extracted with dichloromethane (300ml). The organic layer was washed with brine (100 ml), then dried(Na₂SO₄). After removal of solvent, the crude product was purified byflash column chromatography eluting with hexane/ethyl acetate (2:1) toafford 8.6 g (95%) of the title compound as yellow solids.

[3501]¹H-NMR (CDCl₃) δ: 9.68 (1H, br.s), 8.57 (1H, s), 7.35 (2H, d,J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.17 (1H, s), 4.33 (2H, t, J=7.0 Hz),3.00 (2H, t, J=7.0 Hz), 2.06 (3H, s).

[3502] Step 2.2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate

[3503] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (step 1).

[3504]¹H-NMR (CDCl₃) δ: 7.13-7.16 (3H, m), 7.06 (1H, s), 6.89 (2H, d,J=8.4 Hz), 5.43 (1H, br.s), 4.26 (2H, t, J=7.2 Hz), 3.69 (2H, br.s),2.89 (2H, d, J=7.2 Hz), 2.04 (3H, s).

[3505] Step 3.2-(4-{[5-chloro-2-{[4-(4-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate

[3506] A mixture of2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (step 2, 250 mg, 0.67 mmol), 4-(4-pyridinyl)butanoic acid (200mg, 1 mmol), and WSC (191 mg, 1 mmol) in dichloromethane (7 ml) wasstirred at room temperature for 1.5 h. The mixture was added water (5ml) and extracted with dichloromethane(30 ml). The organic layer waswashed with brine (5 ml), then dried (Na₂SO₄). The solvent was removedunder reduced pressure to afford the title compound as pale brownamorphous.

[3507] MS (EI) m/z: 519 (M+).

[3508] Step 4.2-{4-[6-chloro-2-[3-(4-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3509] A mixture of2-(4-{[5-chloro-2-{[4-(4-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (step 3, 220 mg, 0.42 mmol) and 2N NaOH (15 ml) in ethanol (20ml) was stirred at 40° C. for 7 h. The solvent was removed and theresidue was added water (50 ml). The mixture was extracted with ethylacetate(100 ml). The organic layer was washed with brine (50 ml), thendried (Na₂SO₄). After removal of solvent, the crude product was purifiedby flash column chromatography eluting with dichloromethane:methanol(20:1) to afford 105 mg (54%) of the title compound as pale brown oil.

[3510]¹H-NMR (CDCl₃) δ: 8.40-8.42 (2H, m), 8.10 (1H, s), 7.43 (2H, d,J=8.3 Hz), 7.16-7.19 (3H, m), 7.02 (2H, d, J=6.0 Hz), 4.00 (2H, t, J=6.2Hz), 3.00 (2H, t, J=6.2 Hz), 2.75 (2H, t, J=7.3 Hz), 2.68 (2H, t, J=7.3Hz), 2.11-2.19 (2H, m).

[3511] Step 5.2-{4-[6-chloro-2-[3-(4-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3512] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[6-chloro-2-[3-(4-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimnidazol-1-yl]phenyl}ethanol(step 4).

[3513] m.p.: 80-87° C.

[3514] IR (KBr) v: 1743, 1610, 1517, 1431, 1346, 1161 cm⁻¹.

[3515] MS (ESI) m/z: 657 (MH⁺), 655 ([M−H]⁻).

[3516]¹H-NMR (CDCl₃) δ: 8.32 (2H, d, J=6.0 Hz), 8.09 (1H, s), 7.99 (2H,d, J=8.2 Hz), 7.34 (2H, d, J=8.2 Hz), 7.22 (2H, d, J=8.2 Hz), 7.15 (1H,s), 6.94-7.02 (4H, m), 4.48 (2H, t, J=5.4 Hz), 3.01 (2H, t, J=5.4 Hz),2.74 (2H, t, J=6.0 Hz), 2.54 (2H, t, J=7.9 Hz), 2.44 (3H, s), 2.16-2.21(2H, m).

Example 3402-{4-[6-Chloro-2-[3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3517] Step 1.2-(4-{[5-chloro-2-{[4-(3-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate

[3518] The title compound was prepared according to the proceduredescribed in step 3 of Example 339 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (Example 339, step 2).

[3519]¹H-NMR (CDCl₃) δ: 8.43 (2H, br.s), 7.50-7.71 (2H, m), 7.15-7.28(6H, m), 6.96 (2H, d, J=8.3 Hz), 6.43 (1H, br.s), 4.26 (2H, t, J=7.0Hz), 2.90 (2H, t, J=7.0 Hz), 2.70 (2H, t, J=7.3 Hz), 2.41 (2H, t, J=7.3Hz), 2.03-2.08 (5H, m).

[3520] Step 2.2-{4-[6-chloro-2-[3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3521] The title compound was prepared according to the proceduredescribed in step 4 of Example 339 from2-(4-{[5-chloro-2-{[4-(3-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (step 1).

[3522] MS (EI) m/z: 459 (M⁺).

[3523]¹H-NMR (CDCl₃) δ: 8.33 (1H, d, J=4.4 Hz), 8.09 (1H, s), 7.62 (1H,s), 7.43-7.50 (3H, m), 7.16-7.22 (4H, m), 4.02 (2H, t, J=5.6 Hz), 2.99(2H, t, J=5.6 Hz), 2.74 (2H, t, J=7.5 Hz), 2.64 (2H, t, J=6.6 Hz),2.04-2.13 (2H, m).

[3524] Step 3.2-{4-[6-chloro-2-[3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3525] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[6-chloro-2-[3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 2).

[3526] m.p.: 90-95° C.

[3527] IR (KBr) v: 1743, 1517, 1431, 1346, 1301, 1161, 1130, 1085 cm⁻¹.

[3528] MS (ESI) m/z: 657 (MH⁺), 655 ([M−H]⁻).

[3529]¹H-NMR (CDCl₃) δ: 8.59 (1H, dd, J=1.7 Hz, 5.1 Hz), 8.08 (1H, s),7.95 (2H, d, J=8.3 Hz), 7.86 (1H, d, J=1.7 Hz), 7.54-7.58 (1H, m),7.27-7.34 (5H, m), 7.20 (1H, s), 7.12 (2H, d, J=8.4 Hz), 4.46 (2H, t,J=5.1 Hz), 3.00 (2H, t, J=5.1 Hz), 2.77-2.82 (2H, m), 2.62 (2H, t, J=7.0Hz), 2.43 (3H, s), 1.85-1.91 (2H, m).

Example 3412-{4-[6-Chloro-2-[3-oxo-3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3530] Step 1.2-(4-{[5-chloro-2-{[4-oxo-4-(3-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate

[3531] The title compound was prepared according to the proceduredescribed in step 3 of Example 339 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (Example 339, step 2).

[3532]¹H-NMR (CDCl₃) δ: 9.19 (1H, d, J=2.2 Hz), 8.80 (1H, dd, J=1.8 Hz,3.9 Hz), 8.20 (1H, d, J=7.9 Hz), 7.64 (2H, br.s), 7.44 (1H, dd, J=5.8Hz, 7.9 Hz), 7.28 (1H, s), 7.19 (2H, d, J=8.3 Hz), 7.05 (2H, d, J=8.3Hz), 6.70 (1H, br.s), 4.27 (2H, t, J=7.1 Hz), 3.49 (2H, t, J=5.5 Hz),2.92 (2H, t, J=7.1 Hz), 2.78 (2H, t, J=5.8 Hz), 2.05 (3H, s).

[3533] Step 2.3-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1-(3-pyridinyl)-1-propanone

[3534] The title compound was prepared according to the proceduredescribed in step 4 of Example 339 from2-(4-{[5-chloro-2-{[4-oxo-4-(3-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (step 1).

[3535]¹H-NMR (CDCl₃) δ: 9.05-9.06 (1H, m), 8.77-8.79 (1H, m), 8.24-8.28(1H, m), 8.06 (1H, s), 7.54 (2H, d, J=8.5 Hz), 7.40-7.46 (3H, m),3.97-4.04 (2H, m), 3.66 (2H, t, J=7.0 Hz), 3.19 (2H, t, J=7.0 Hz), 3.02(2H, t, J=6.4 Hz).

[3536] Step 3.2-{4-[6-chloro-2-[3-oxo-3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3537] The title compound was prepared according to the proceduredescribed in Example 3 from3-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1-(3-pyridinyl)-1-propanone(step 2).

[3538] m.p.: 89-95° C.

[3539] IR (KBr) v: 2972, 1747, 1693, 1517, 1346, 1230, 1161, 1085 cm⁻¹.

[3540] MS (ESI) m/z: 671 (MH⁺), 669 ([M−H]⁻).

[3541]¹H-NMR (CDCl₃) δ: 8.91 (1H, s), 8.83-8.85 (1H, m), 8.23-8.27 (1H,m), 8.05 (1H, s), 7.92 (2H, d, J=8.2 Hz), 7.33-7.48 (7H, m), 7.21 (1H,s), 4.43 (2H, t, J=6.3 Hz), 3.47 (2H, t, J=7.1 Hz), 3.25 (2H, t, J=7.1Hz), 3.04 (2H, t, J=6.3 Hz), 2.43 (3H, s).

Example 3422-{4-[6-Chloro-2-[3-oxo-3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3542] Step 1.2-(4-{[5-chloro-2-{[4-oxo-4-(2-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate

[3543] The title compound was prepared according to the proceduredescribed in step 3 of Example 339 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (Example 339, step 2).

[3544] MS (EI) m/z: 533 (M⁺).

[3545] Step 2.3-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1-(2-pyridinyl)-1-propanone

[3546] The title compound was prepared according to the proceduredescribed in step 4 of Example 339 from2-(4-{[5-chloro-2-{[4-oxo-4-(2-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (step 1).

[3547]¹H-NMR (CDCl₃) δ: 8.67-8.69 (1H, m), 7.84 (1H, s), 7.96-7.99 (1H,m), 7.81-7.84 (1H, m), 7.39-7.51 (5H, m), 7.23 (1H, s), 3.96-4.02 (2H,m), 3.91 (2H, t, J=6.9 Hz), 3.15 (2H, t, J=6.9 Hz), 3.01 (2H, t, J=6.4Hz).

[3548] Step 3.2-{4-[6-chloro-2-[3-oxo-3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3549] The title compound was prepared according to the proceduredescribed in of Example 3 from3-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1-(2-pyridinyl)-1-propanone(step 2).

[3550] m.p.: 233.6° C.

[3551] IR (KBr) v: 1743, 1703, 1515, 1481, 1336, 1203, 1120, 1087, 995cm⁻¹.

[3552] MS (ESI) m/z: 671 (MH⁺), 669 ([M−H]⁻).

[3553]¹H-NMR (DMSO-d₆) δ: 8.74-8.76 (1H, m), 8.13 (1H, S), 7.90-8.03(2H, m), 7.77 (2H, d, J=8.1 Hz), 7.66-7.70 (1H, m), 7.49-7.58 (4H, m),7.42 (2H, d, J=8.1 Hz), 7.34 (1H, s), 4.30 (2H, t, J=6.4 Hz), 3.83 (2H,t, J=6.4 Hz), 3.09 (2H, t, J=6.4 Hz), 2.98 (2H, t, J=6.4 Hz), 2.50 (3H,s).

Example 3432-{4-[6-Chloro-2-[3-(2pyridinyl)propyl]-5-(trifluoromrthyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3554] Step 1.2-(4-{[5-chloro-2-{[4-(2-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]aminolphenyl)ethylacetate

[3555] The title compound was prepared according to the proceduredescribed in step 3 of Example 339 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (Example 339, step 2).

[3556]¹H-NMR (CDCl₃) δ: 9.26 (1H, br.s), 8.39-8.41 (1H, m), 7.86 (1H,s), 7.69-7.72 (1H, m), 7.49 (1H, s), 7.25-7.28 (1H, m), 7.15-7.21 (3H,m), 7.00 (2H, d, J=8.4 Hz), 4.27 (2H, t, J=7.1 Hz), 2.98 (2H, t, J=6.3Hz), 2.91 (2H, t, J=7.1 Hz), 2.33 (2H, t, J=5.9 Hz), 2.05 (3H, s).

[3557] Step 2.2-{4-[6-chloro-2-[3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3558] The title compound was prepared according to the proceduredescribed in step 4 of Example 339 from2-(4-{[5-chloro-2-{[4-(2-pyridinyl)butanoyl]amino}4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (step 1).

[3559]¹H-NMR (CDCl₃) δ: 8.43-8.45 (1H, m), 8.09 (1H, s), 7.53-7.59 (1H,m), 7.45 (2H, d, J=8.2 Hz), 7.22-7.25 (3H, m), 7.05-7.13 (2H, m), 3.98(2H, t, J=6.3 Hz), 3.00 (2H, t, J=6.3 Hz), 2.84 (4H, t, J=7.5 Hz),2.18-2.22 (2H, m), 1.81-1.90 (2H, m).

[3560] Step 3.2-{4-[6-chloro-2-[3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3561] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[6-chloro-2-[3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 2).

[3562] m.p.: 193° C.

[3563] IR (KBr) v: 1747, 1626, 1517, 1433, 1350, 1159, 1120, 1085 cm⁻¹.

[3564] MS (ESI) m/z: 657 (MH⁺), 655 ([M−H]⁻).

[3565]¹H-NMR (CDCl₃) δ: 8.47-8.49 (1H, m), 8.08 (1H, s), 7.90 (2H, d,J=8.4 Hz), 7.60-7.66 (1H, m), 7.36 (2H, d, J=8.4 Hz), 7.11-7.22 (7H, m),4.44 (2H, t, J=6.0 Hz), 3.01 (2H, t, J=6.0 Hz), 2.82-2.88 (4H, m), 2.45(3H, s), 1.84-1.94 (2H, m).

Example 3442-{4-[6-Chloro-2-[3-(2pyridinyl)propyl]-5-(trifluoromrthyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate p-toluenesulfonate

[3566] The title compound was prepared according to the proceduredescribed in Example 231 from2-{4-[6-chloro-2-[3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate (Example 343)

[3567] m.p.: 108-110° C.

[3568] IR (KBr) v: 3062, 1745, 1456, 1232, 1163, 1010 cm⁻¹.

Example 345N-{[(2-{4-[2-Ethyl-5-(1-hydroxethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3569] Step 1.N-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3570] A mixtureN-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide(Example 78, 238 mg, 0.47 mmol) and 2N NaOH (0.1 ml) in ethanol (10 ml)was added a mixture of NaBH₄ (178 mg, 0.47 mmol) and 2N NaOH (0.1 ml) inethanol (4 ml) at room temperature. The mixture was stirred at roomtemperature for 4 h. The mixture was added water (10 ml) and neutralizedwith NH₄Cl. The mixture was extracted with ethyl acetate(50 ml). Theorganic layer was washed with brine (10 ml), then dried (Na₂SO₄). Afterremoval of solvent, the crude product was purified by flash columnchromatography eluting with hexane/ethyl acetate(1:4/1:6)/CH₂Cl₂:methanol(10:1) to afford 198 mg (83%) of the titlecompound as white solids.

[3571] m.p.: 190° C.

[3572] IR (KBr) v: 3384, 2979, 1716, 1514, 1404, 1159, 1087 cm⁻¹.

[3573] MS (ESI) m/z: 507 (MH⁺), 505 ([M−H]⁻).

[3574]¹H-NMR (CDCl₃) δ: 7.73-7.76 (3H, m), 7.21-7.34 (7H, m), 7.20 (1H,d, J=8.5 Hz), 6.66 (1H, br.s), 5.02 (1H, q, J=6.4 Hz), 3.52-3.59 (2H,m), 2.91 (2H, t, J=7.0 Hz), 2.75 (2H, q, J=7.5 Hz), 2.39 (3H, s), 1.54(3H, d, J=6.4 Hz), 1.30 (3H, t, J=7.5 Hz).

Example 346N-{[(2-{4-[2-Ethyl-5-(1-hydroxethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl[-4-methylbenzenesulfonamidep-toluenesulfonate

[3575] The title compound was prepared according to the proceduredescribed in Example 231 fromN-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(Example 345)

[3576] m.p.: 110-115° C.

[3577] IR (KBr) v: 3062, 1708, 1519, 1340, 1163 cm⁻¹.

Example 347N-({[2-(4-{2-Ethyl-5-[1-(methyloxy)ethyl]-1H-benzimidazol-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide

[3578] Step 1.N-({[2-(4-2-ethyl-5-[1-(methyloxy)ethyl]-1H-benzimidazol-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide

[3579] A solution ofN-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(Example 345, 151 mg, 0.3 mmol) in CH₂Cl₂ (15 ml) was added thionylchloride (0.1 ml, 1.5 mmol) at room temperature. The mixture was stirredat room temperature for 2 h. The solvent was removed and the residue wasdissolved with methanol (15 ml). The mixture was added triethylamine(0.08 ml, 0.6 mmol) and stirred at room temperature for 5 h. The solventwas removed and the residue was extracted with CH₂Cl₂ (50 ml). Theorganic layer was washed with water(10 ml), brine (10 ml), then dried(Na₂SO₄). After removal of solvent, the crude product was purified byflash column chromatography eluting with hexane/ethyl acetate(1:6)/CH₂Cl₂:methanol(10:1) to afford 139 mg (89%) of the title compoundas white solids.

[3580] MS (ESI) m/z: 521 (MH⁺), 519 ([M−H]⁻).

[3581]¹H-NMR (CDCl₃) δ: 7.65-7.75 (3H, m), 7.27-7.37 (6H, m), 7.16-7.20(1H, m), 7.07 (1H, d, J=8.3 Hz), 6.69 (1H, br.s), 4.42 (1H, q, J=6.5Hz), 3.54-3.62 (2H, m), 3.22 (3H, s), 2.93 (2H, t, J=7.0 Hz), 2.93 (2H,t, J=7.0 Hz), 2.78 (2H, q, J=7.6 Hz), 2.39 (3H, s), 1.49 (3H, d, J=6.5Hz), 1.32 (3H, t, J=7.6 Hz).

Example 348N-({[2-(4-{2-Ethyl-5-[1-(methyloxy)ethyl]-1H-benzimidazol-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamidep-toluenesulfonate

[3582] The title compound was prepared according to the proceduredescribed in Example 231 fromN-({[2-(4-{2-ethyl-5-[1-(methyloxy)ethyl]-1H-benzimidazol-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide(Example 347)

[3583] m.p.: 110-115° C.

[3584] IR (KBr) v: 3064, 1710, 1519, 1452, 1340, 1163, 1033 cm⁻¹.

Example 349N-{[(2-{4-[2-Ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamideP-toluenesulfonate

[3585] Step 1.N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3586] A solution ofN-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide(Example 78, 100 mg, 0.19 mmol) in tetrahydrofurane (15 ml) was addedMeMgI (1.2 ml, 0.99 mmol) dropwise under nitrogen at 0° C. The mixturewas stirred at 0° C. for 1 h and then was stirred at rt for 30 min. Themixture was added water (10 ml) and extracted with CH₂Cl₂(50 ml). Theorganic layer was washed with brine (10 ml), then dried (Na₂SO₄). Afterremoval of solvent, the crude product was purified by flash columnchromatography eluting with CH₂Cl₂:methanol (30:1/20:1/10:1) to afford100 mg (97%) of the title compound as white solids.

[3587] MS (ESI) m/z: 521 (MH⁺), 519 ([M−H]⁻).

[3588]¹H-NMR (CDCl₃) δ: 7.87 (1H, s), 7.76 (2H, d, J=7.9 Hz), 7.17-7.38(7H, m), 7.00 (1H, d, J=8.5 Hz), 6.69 (1H, br.s), 3.52 (2H, br.s), 2.88(2H, br.s), 2.73 (2H, br.s), 2.36 (3H, s), 1.62 (6H, s), 1.27 (3H, m).

[3589] Step 2.N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamidep-toluenesulfonate

[3590] The title compound was prepared according to the proceduredescribed in Example 231 fromN-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(Step 1).

[3591] m.p.: 146-150° C.

[3592] IR (KBr) v: 2871, 1685, 1519, 1448, 1340, 1124 cm⁻¹.

Example 3502-Ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

[3593] Step 1.1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide

[3594] A solution of1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile(Example 329, step 6, 997 mg, 2.95 mmol) in c.H₂SO₄ (50 ml) was stirredat 80° C. for 15 h. The mixture was poured onto ice and was neutralizedwith NaOH. The mixture was extracted with ethyl acetate (600 ml). Theorganic layer was washed with brine (300 ml), then dried (Na₂SO₄). Thesolvent was removed to afford 871 mg (83%) of the title compound aswhite solids.

[3595] MS (EI) m/z: 355 (M+).

[3596]¹H-NMR (CDCl₃) δ: 7.43 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz),6.73 (1H, s), 6.56 (1H, br.s), 5.88 (1H, br.s), 3.82 (2H, t, J=7.0 Hz),3.19 (2H, t, J=7.0 Hz), 2.82 (2H, q, J=7.6 Hz), 2.72 (3H, s), 2.41 (3H,s), 1.26 (3H, t, J=7.6 Hz).

[3597] Step 2.1-[4-(2-azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide

[3598] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide(step 1).

[3599]¹H-NMR (CDCl₃) δ: 7.44 (2H, d, J=8.4 Hz), 7.27-7.30 (2H, m), 6.73(1H, s), 5.97 (1H, br.s), 5.72 (1H, br.s), 3.62 (2H, t, J=7.1 Hz), 3.02(2H, t, J=7.1 Hz), 2.80 (2H, q, J=7.5 Hz), 2.73 (3H, s), 2.42 (3H, s),1.26 (3H, t, J=7.5 Hz).

[3600] Step 3.1-[4-(2-aminoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide

[3601] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from1-[4-(2-azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide(step 2).

[3602]¹H-NMR (CDCl₃) δ: 7.41 (2H, d, J=8.2 Hz), 7.26 (2H, d, J=8.2 Hz),6.74 (1H, s), 6.00 (1H, br.s), 5.76 (1H, br.s), 3.07 (2H, t, J=7.1 Hz),2.87 (2H, t, J=7.1 Hz), 2.81 (2H, q, J=7.5 Hz), 2.74 (3H, s), 2.43 (3H,s), 1.26 (3H, t, J=7.5 Hz).

[3603] Step 4.2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

[3604] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-[4-(2-aminoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide(step 3).

[3605] MS (ESI) m/z: 534 (MH⁺), 532 ([M−H]⁻).

[3606]¹H-NMR (CD₃OD) δ: 7.88 (1H, s), 7.80 (2H, d, J=8.3 Hz), 7.25-7.42(6H, m), 6.74 (1H, br.s), 3.42 (2H, t, J=6.8 Hz), 2.86 (2H, t, J=6.8Hz), 2.79 (2H, q, J=7.6 Hz), 2.65 (3H, s), 2.37 (3H, s), 2.34 (3H, s),1.21 (3H, t, J=7.6 Hz).

[3607] Step 5.2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamidep-toluenesulfonate

[3608] The title compound was prepared according to the proceduredescribed in Example 231 from2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide(step 4).

Example 351N-{[(2-{4-[2-Ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamideP-toluenesulfonate

[3609] Step 1.2,2,2-trifluoro-1-(4-{[4-(2-hydroxyethyl)phenyl]amino}-3-nitrophenyl)ethanone

[3610] The title compound was prepared according to the proceduredescribed in step 1 of Example 45 from1-(4-amino-3-nitrophenyl)-2,2,2-trifluoroethanone.

[3611]¹H-NMR (CDCl₃) δ: 9.47 (1H, br.s), 8.10 (1H, d, J=2.6 Hz),7.16-7.33 (6H, m), 3.87-3.94 (2H, m), 2.91 (2H, t, J=6.4 Hz), 1.43 (1H,t, J=5.6 Hz).

[3612] Step 2.1-(3-amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)-2,2,2-trifluoroethanone

[3613] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from2,2,2-trifluoro-1-(4-{[4-(2-hydroxyethyl)phenyl]amino}-3-nitrophenyl)ethanone(step 1).

[3614]¹H-NMR (CDCl₃) δ: 7.05-7.09 (3H, m), 6.57-6.70 (4H, m), 3.82 (2H,t, J=6.6 Hz), 2.78 (2H, t, J=6.6 Hz).

[3615] Step 3.2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethylpropanoate

[3616] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from1-(3-amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)-2,2,2-trifluoroethanone(step 2).

[3617]¹H-NMR (CDCl₃) δ: 7.65 (1H, s), 7.45 (2H, d, J=8.3 Hz), 7.29 (2H,d, J=8.3 Hz), 7.06 (2H, s), 4.38 (2H, t, J=6.9 Hz), 3.07 (2H, t, J=6.9Hz), 2.79 (2H, q, J=7.4 Hz), 2.35 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.4Hz), 1.14 (3H, t, J=7.5 Hz).

[3618] Step 4.1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone

[3619] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethylpropanoate (step 3).

[3620]¹H-NMR (CDCl₃) δ:7.65 (1H, s), 7.47 (2H, d, J=8.4 Hz), 7.29 (2H,d, J=8.4 Hz), 7.06 (2H, s), 3.96-4.03 (2H, m), 3.01 (2H, t, J=6.6 Hz),2.79 (2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.6 Hz).

[3621] Step 5.1-{1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone

[3622] The title compound was prepared according to the proceduredescribed in step 7 Example 1 from1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone(step 4).

[3623]¹H-NMR (CDCl₃) δ: 7.66 (1H, s), 7.45 (2H, d, J=8.4 Hz), 7.31 (2H,d, J=8.4 Hz), 7.07 (2H, s), 3.82 (2H, t, J=7.0 Hz), 3.20 (2H, t, J=7.0Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).

[3624] Step 6.1-{1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-2.2,2-trifluoroethanone

[3625] The title compound was prepared according to the proceduredescribed in step 8 Example 1 from1-{1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone(step 5).

[3626]¹H-NMR (CDCl₃) δ: 7.65 (1H, s), 7.46 (2H, d, J=8.4 Hz), 7.31 (2H,d, J=8.4 Hz), 7.06 (1H, s), 3.62 (2H, t, J=7.0 Hz), 3.02 (2H, t, J=7.0Hz), 2.79 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.5 Hz).

[3627] Step 7.1-{1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone

[3628] The title compound was prepared according to the proceduredescribed in step 9 of Example 1 from1-{1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone(step 6).

[3629]¹H-NMR (CDCl₃) δ:7.65 (1H, s), 7.43 (2H, d, J=8.5 Hz), 7.28 (2H,d, J=8.5 Hz), 7.07 (2H, s), 3.09 (2H, t, J=6.7 Hz), 2.89 (2H, t, J=6.7Hz), 2.79 (2H, q, J=7.4 Hz), 1.35 (3H, t, J=7.4 Hz).

[3630] Step 8.N-{[(2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3631] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from1-{1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone(step 7).

[3632] MS (ESI) m/z: 547 (MH⁺), 545 ([M−H]⁻).

[3633]¹H-NMR (CDCl₃) δ: 7.72 (2H, d, J=8.4 Hz), 7.64 (1H, s), 7.39 (2H,d, J=8.4 Hz), 7.27-7.29 (4H, m), 7.02-7.04 (2H, m), 6.75 (1H, br.s),3.55-3.62 (2H, m), 2.94 (2H, t, J=6.9 Hz), 2.79 (2H, q, J=7.5 Hz), 2.39(3H, s), 1.33 (3H, t, J=7.5 Hz).

[3634] Step 9.N-{[(2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamidep-toluenesulfonate

[3635] The title compound was prepared according to the proceduredescribed in Example 231 fromN-{[(2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(step 8)

[3636] m.p.: 194.1° C.

[3637] IR (KBr) v: 3589, 1701, 1627, 1521, 1458, 1330, 1091 cm⁻¹.

Example 3522-{4-[2-Ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamateP-toluenesulfonate

[3638] Step 1.2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3639] The title compound was prepared according to the proceduredescribed in Example 3 from1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone(Example 351, step 4).

[3640] MS (ESI) m/z: 548 (MH⁺), 546 ([M−H]⁻).

[3641]¹H-NMR (CDCl₃) δ: 7.93 (2H, d, J=8.4 Hz), 7.64(1H, s), 7.28-7.35(4H, m), 7.20 (2H, d, J=8.4 Hz), 7.05-7.07 (2H, m), 4.37 (2H, t, J=6.6Hz), 3.00 (2H, t, J=6.6 Hz), 2.76 (2H, q, J=7.6 Hz), 2.43 (3H, s), 1.31(3H, t, J=7.6 Hz).

[3642] Step 2.2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamatep-toluenesulfonate

[3643] The title compound was prepared according to the proceduredescribed in Example 231 from2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate(Step 1)

[3644] m.p.: 92-97° C.

[3645] IR (KBr) v: 1745, 1519, 1458, 1350, 1222, 1163, 1122 cm⁻¹.

Example 3532-{4-[5-Acetyl-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamateP-toluenesulfonate

[3646] Step 1.1-[1-[4-(2-hydroxyethyl)phenyl]-2-(1H-pyrazol-3-yl)-1H-benzimidazol-5-yl]ethanone

[3647] The title compound was prepared according to the proceduredescribed in step 1 of Example 236 from1-(3-amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)ethanone (Example78, step 2).

[3648] MS (EI) m/z: 345 (M+).

[3649]¹H-NMR (CDCl₃) δ: 8.53 (1H, s), 7.94 (1H, d, J=8.4 Hz), 7.48-7.53(3H, m), 7.37 (2H, d, J=8.2 Hz), 7.27 (1H, s), 7.18 (1H, d, J=8.4 Hz),6.03 (1H, br.s), 4.02 (2H, t, J=6.6 Hz), 3.05 (2H, t, J=6.6 Hz), 2.69(3H, s).

[3650] Step 2.2-{4-[5-acetyl-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3651] The title compound was prepared according to the proceduredescribed in Example 3 from1-[1-[4-(2-hydroxyethyl)phenyl]-2-(1H-pyrazol-3-yl)-1H-benzimidazol-5-yl]ethanone(step 1).

[3652] MS (ESI) m/z: 544 (MH⁺), 542 ([M−H]⁻).

[3653]¹H-NMR (DMSO-d₆) δ: 8.41 (1H, s), 7.77-7.89 (4H, m), 7.38-7.42(7H, m), 7.12 (1H, d, J=8.5 Hz), 6.65 (1H, br.s), 4.29 (2H, t, J=6.6Hz), 2.96 (2H, t, J=6.6 Hz), 2.66 (3H, s), 2.35 (3H, s).

[3654] Step 3.2-{4-[5-acetyl-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamatep-toluenesulfonate

[3655] The title compound was prepared according to the proceduredescribed in Example 231 from2-{4-[5-acetyl-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate(step 2)

[3656] m.p.: 204° C.

[3657] IR (KBr) v: 3249, 1755, 1676, 1595, 1517, 1440, 1332, 1207, 1161,1008 cm⁻¹.

Example 354N-{[(2-{4-[6-Chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamideP-toluenesulfonate

[3658] Step 1.2-(4-{[5-chloro-2-[(2-hydroxypropanoyl)amino]-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate

[3659] The title compound was prepared according to the proceduredescribed in step 3 of Example 339 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (Example 339, step 2).

[3660] MS (EI) m/z: 444 (M⁺).

[3661] Step 2.2-{4-[6-chloro-2-(1-hydroxyethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylacetate

[3662] The title compound was prepared according to the proceduredescribed in step 4 of Example 339 from2-(4-{[5-chloro-2-[(2-hydroxypropanoyl)amino]-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (step 1)

[3663]¹H-NMR (CDCl₃) δ: 8.14 (1H, s), 7.48 (2H, d, J=8.4 Hz), 7.34 (2H,d, J=8.4 Hz), 7.24 (1H, s), 4.88-4.98 (1H, m), 4.38 (2H, t, J=7.0 Hz),3.66 (1H, d, J=8.1 Hz), 3.08 (2H, t, J=7.0 Hz), 2.09 (3H, s), 1.57 (3H,d, J=6.6 Hz).

[3664] Step 3.1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol

[3665] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[6-chloro-2-(1-hydroxyethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylacetate (step 2)

[3666] MS (ESI) m/z: 384 (M⁺).

[3667]¹H-NMR (CDCl₃) δ: 8.14 (1H, s), 7.49 (2H, d, J=8.6 Hz), 7.34 (2H,d, J=8.6 Hz), 7.25 (1H, s), 4.89-4.96 (1H, m), 3.98 (2H, t, J=6.2 Hz),3.36 (1H, d, J=5.5 Hz), 3.01 (2H, t, J=6.2 Hz), 1.54 (3H, m).

[3668] Step 4.1-[6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol

[3669] A mixture of1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol(step 3, 461 mg, 1.19 mmol), tert-Butyldiphenylsilyl chloride (0.35 ml,1.3 mmol), triethylamine (0.2 ml, 1.4 mmol) andN,N-dimethylaminopyridine (6 mg, 0.05 mmol) in dichloromethane (11 ml)was stirred under nitrogen at room temperature for 4 h. was added water(50 ml) and extracted with dichloromethane (100 ml). The organic layerwas washed with water (50 ml), brine (50 ml), then dried (Na₂SO₄). Afterremoval of solvent, the crude product was purified by flash columnchromatography eluting with hexane/ethyl acetate (3:1/1:1) to afford 590mg (80%) of the title compound as white amorphous.

[3670]¹H-NMR (CDCl₃) δ: 8.14 (1H, s), 7.59-7.63 (4H, m), 7.34-7.46 (8H,m), 7.22-7.30 (3H, m), 4.87-4.96 (1H, m), 3.94 (2H, t, J=6.4 Hz), 3.29(1H, d, J=8.1 Hz), 2.97 (2H, t, J=6.4 Hz), 1.52 (3H, d, J=6.6 Hz), 1.03(9H, s).

[3671] Step 5.6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)phenyl]-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazole

[3672] A solution of1-[6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol(step 4, 590 mg, 0.95 mmol) in DMF (10 ml) was added NaH (45 mg, 1.13mmol). Then the mixture was added MeI (0.08 ml, 1.23 mmol) at roomtemperature. The mixture was stirred at room temperature for 1 h. Themixture was added water (30 ml) and extracted with ethyl acetate (100ml). The organic layer was washed with water (50 ml), brine (50 ml),then dried (Na₂SO₄). After removal of solvent, the crude product waspurified by flash column chromatography eluting with hexane/ethylacetate (3:1) to afford 550 mg (91%) of the title compound as colorlessoil.

[3673]¹H-NMR (CDCl₃) δ:8.17 (1H, s), 7.20-7.70 (15H, m), 4.54 (1H, q,J=6.6 Hz), 3.95 (2H, t, J=6.6 Hz), 3.22 (3H, s), 2.97 (2H, t, J=6.6 Hz),1.55 (3H, d, J=6.6 Hz), 1.03 (9H, s).

[3674] Step 6.2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3675] The title compound was prepared according to the proceduredescribed in step 6 of Example 90 from6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)phenyl]-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazole(step 5).

[3676] MS (ESI) m/z:398.

[3677]¹H-NMR (CDCl₃) δ:8.18 (1H, s), 7.49 (2H, d, J=8.4 Hz), 7.33 (2H,d, J=8.4 Hz), 7.24 (1H, s), 4.58 (1H, q, J=6.6 Hz), 4.00 (2H, br.s),3.24 (3H, s), 3.02 (2H, t, J=6.5 Hz), 1.55-1.60 (3H, m).

[3678] Step 7.6-chloro-1-[4-(2-chloroethyl)phenyl]-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazole

[3679] The title compound was prepared according to the proceduredescribed in step 7 of Example 1 from2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 6).

[3680] MS (ESI) m/z:416 (M⁺).

[3681]¹H-NMR (CDCl₃) δ: 8.18 (1H, s), 7.48 (2H, d, J=8.5 Hz), 7.35 (2H,d, J=8.5 Hz), 7.23 (1H, s), 5.57 (1H, q, J=6.6 Hz), 3.83 (2H, t, J=7.1Hz), 3.19-3.24 (5H, m), 1.57 (3H, d, J=6.6 Hz).

[3682] Step 8.1-[4-(2-azidoethyl)phenyl]-6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazole

[3683] The title compound was prepared according to the proceduredescribed in step 8 of Example 1 from6-chloro-1-[4-(2-chloroethyl)phenyl]-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazole(step 7).

[3684] MS (ESI) m/z:423 (M⁺).

[3685]¹H-NMR (CDCl₃) δ: 8.18 (1H, s), 7.48 (2H, d, J=8.2 Hz), 7.35 (2H,d, J=8.2 Hz), 7.22 (1H, s), 4.57 (1H, q, J=6.6 Hz), 3.63 (2H, t, J=6.9Hz), 3.23 (3H, s), 3.04 (2H, t, J=6.9 Hz), 1.56 (3H, d, J=6.6 Hz).

[3686] Step 9.2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanamine

[3687] The title compound was prepared according to the proceduredescribed in step 7 of Example 37 from1-[4-(2-azidoethyl)phenyl]-6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazole(step 8).

[3688]¹H-NMR (CDCl₃) δ: 8.18 (1H, s), 7.45 (2H, d, J=8.4 Hz), 7.32 (2H,d, J=8.4 Hz), 7.24 (1H, s), 4.57 (1H, q, J=6.6 Hz), 3.23 (3H, s), 3.10(2H, br.s), 2.90 (2H, t, J=6.6 Hz), 1.57 (3H, d, J=6.6 Hz).

[3689] Step 10.N-{[(2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3690] The title compound was prepared according to the proceduredescribed in step 10 of Example 1 from2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanamine(step 9).

[3691] MS (ESI) m/z: 595 (MH⁺), 593 ([M−H]⁻).

[3692]¹H-NMR (CDCl₃) δ: 8.18 (1H, s), 7.73 (2H, d, J=8.4 Hz), 7.42 (2H,d, J=8.6 Hz), 7.27-7.34 (4H, m), 7.21 (1H, s), 6.76 (1H, br.s), 4.57(1H, q, J=6.6 Hz), 3.56-3.63 (2H, m), 3.23 (3H, s), 2.96 (2H, t, J=7.1Hz), 2.41 (3H, s), 1.56 (3H, d, J=6.6 Hz).

[3693] Step 11.N-{[(2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamidep-toluenesulfonate

[3694] The title compound was prepared according to the proceduredescribed in Example 231 fromN-{[(2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(step 10)

[3695] IR (KBr) v: 2873, 1712, 1517, 1454, 1342, 1122, 1033, 1010 cm⁻¹.

Example 3552-{4-[2-Ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamateP-toluenesulfonate

[3696] Step 1.2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3697] The title compound was prepared according to the proceduredescribed in Example 345 from2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate (Example 332)

[3698] MS (ESI) m/z: 508 (MH⁺), 506 ([M−H]⁻).

[3699]¹H-NMR (CDCl₃) δ: 7.94 (2H, d, J=8.3 Hz), 7.77 (1H, s), 7.03-7.35(8H, m), 5.04 (1H, q, J=6.4 Hz), 4.36 (2H, t, J=6.6 Hz), 2.97 (2H, t,J=6.6 Hz), 2.74 (2H, q, J=7.5 Hz), 2.43 (3H, s), 1.56 (3H, d, J=6.4 Hz),1.28 (3H, t, J=7.5 Hz).

[3700] Step 2.2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamatep-toluenesulfonate

[3701] The title compound was prepared according to the proceduredescribed in Example 231 from2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate(step 1)

[3702] m.p.: 96-110° C.

[3703] IR (KBr) v: 1743, 1519, 1456, 1163, 1033, 1010 cm⁻¹.

Example 3562-{4-[2-Ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamateP-toluenesulfonate

[3704] Step 1.2-(4-{[3-methyl-4-(methyloxy)-2-nitrophenyl]amino}phenyl)ethanol

[3705] The title compound was prepared according to the proceduredescribed in step 3 of Example 1 from1-chloro-3-methyl-4-(methyloxy)-2-nitrobenzene

[3706] MS (EI) m/z: 302 (M⁺).

[3707]¹H-NMR (CDCl₃) δ: 7.11-7.20 (3H, m), 6.89-6.96 (3H, m), 6.53 (1H,br.s), 3.83 (5H, br.s), 2.81 (2H, t, J=6.4 Hz), 2.25 (3H, s).

[3708] Step 2.2-(4-{[2-amino-3-methyl-4-(methyloxy)phenyl]amino}phenyl)ethanol

[3709] The title compound was prepared according to the proceduredescribed in step 4 of Example 1 from2-(4-{[3-methyl-4-(methyloxy)-2-nitrophenyl]amino}phenyl)ethanol (step1).

[3710] MS (EI) m/z: 272 (M⁺).

[3711]¹H-NMR (CDCl₃) δ: 7.03 (2H, d, J=8.6 Hz), 6.92 (1H, d, J=8.6 Hz),6.57 (2H, d, J=8.6 Hz), 6.32 (2H, d, J=8.6 Hz), 5.01 (1H, br.s),3.77-3.90 (7H, m), 2.76 (2H, t, J=6.4 Hz), 2.09 (3H, s).

[3712] Step 3.2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]phenyl}ethylpropanoate

[3713] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-(4-{[2-amino-3-methyl-4-(methyloxy)phenyl]amino}phenyl)ethanol (step2).

[3714] MS (EI) m/z: 366 (M⁺).

[3715] Step 4.2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]phenyl}ethanol

[3716] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]phenyl}ethylpropanoate (step 3).

[3717]¹H-NMR (CDCl₃) δ:7.42 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz),6.84 (2H, s), 3.97 (2H, t, J=6.4 Hz), 3.86 (3H, s), 2.99 (2H, t, J=6.4Hz), 2.81 (2H, q, J=7.7 Hz), 2.58 (3H, s), 1.26 (3H, t, J=7.7 Hz).

[3718] Step 5.2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3719] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]phenyl}ethanol(step 4).

[3720] MS (ESI) m/z: 508 (MH⁺), 506 ([M−H]⁻).

[3721]¹H-NMR (CDCl₃) δ: 7.98 (2H, d, J=8.3 Hz), 7.33 (2H, d, J=8.9 Hz),6.88-6.91 (6H, m), 4.28 (2H, t, J=6.0 Hz), 3.89 (3H, s), 2.84 (2H, t,J=6.0 Hz), 2.74 (2H, q, J=7.5 Hz), 2.56 (3H, s), 2.43 (3H, s), 1.05 (3H,t, J=7.5 Hz).

[3722] Step 6.2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamatep-toluenesulfonate

[3723] The title compound was prepared according to the proceduredescribed in Example 231 from2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate(step 5)

[3724] m.p.: 94-103° C.

[3725] IR (KBr) v: 1747, 1458, 1232, 1163, 1120 cm⁻¹.

Example 3572-[4-(2-Ethyl-5-phenyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3726] Step 1. 2-{4-[(4-bromo-2-nitrophenyl)amino]phenyl}ethanol

[3727] The title compound was prepared according to the proceduredescribed in step 1 of Example 162 from 2,5-dibromonitrobenzene.

[3728]¹H-NMR (CDCl₃) δ: 9.43 (1H, br.s), 8.34 (1H, d, J=2.4 Hz),7.43-7.39 (1H, m), 7.30 (2H, d, J=8.3 Hz), 7.20 (2H, d, J=8.3 Hz), 7.08(1H, d, J=9.2 Hz), 3.94-3.88 (2H, m), 2.90 (2H, d, J=6.4 Hz), 1.43 (1H,t, J=5.7 Hz).

[3729] Step 2. 2-{4-[(2-amino-4-bromophenyl)amino]phenyl}ethanol

[3730] The title compound was prepared according to the proceduredescribed in step 2 of Example 28 from2-{4-[(4-bromo-2-nitrophenyl)amino]phenyl}ethanol (step 1).

[3731]¹H-NMR (CDCl₃) δ: 7.08 (2H, d, J=8.4 Hz), 6.97-6.93 (2H, m), 6.84(1H, dd, J=8.3, 2.2 Hz), 6.69 (2H, d, J=8.6 Hz), 5.04 (1H, br.s), 3.80(2H, br.s), 3.82 (2H, t, J=6.4 Hz), 2.79 (2H, t, J=6.4 Hz).

[3732] Step 3. 2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylpropionate

[3733] The title compound was prepared according to the proceduredescribed in step 5 of Example 1 from2-{4-[(2-amino-4-bromophenyl)amino]phenyl}ethanol (step 2).

[3734] MS (EI) m/z 401 (M⁺).

[3735] Step 4. 2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol

[3736] The title compound was prepared according to the proceduredescribed in step 6 of Example 1 from2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step3).

[3737]¹H-NMR (CDCl₃) δ: 7.90 (1H, s), 7.45 (2H, d, J=8.1 Hz), 7.26-7.30(3H, m), 6.96 (1H, d, J=8.4 Hz), 3.98 (2H, m), 3.00 (2H, t, J=6.4 Hz),2.78 (2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz).

[3738] Step 5.2-[4-(2-ethyl-5-phenyl-1H-benzimidazol-1-yl)phenyl]ethanol

[3739] To a solution of2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4, 116mg, 0.57 mmol) in 1,2-dimethoxyethane (DME, 6 ml) was added PhB(OH)₂(141 mg, 1.16 mmol), K₂CO₃ (240 mg, 1.75 mmol) and Pd(PPh₃)₄ (67 mg,0.06 mmol). This mixture was stirred at 95° C. for 11 h. The reactionmixture was diluted with water and extracted with CH₂Cl₂ (4×10 ml). Theorganic layer was dried (MgSO₄) and concentrated to give brown oil. Thismixture was purified by SiO₂ preparative TLC (hexane/ethyl acetate=1/5)to afford 52 mg (27%) of the title compound.

[3740] MS (EI) m/z 342 (M⁺).

[3741]¹H-NMR (CDCl₃) δ: 8.00 (1H, d, J=1.6 Hz), 7.65 (2H, dd, J=1.6, 8.4Hz), 7.42-7.48 (5H, m), 7.32-7.35 (3H, m), 7.15 (2H, d, J=8.4 Hz), 4.00(2H, brt), 3.01 (2H, t, J=6.5 Hz), 2.82 (2H, q, J=7.6 Hz), 1.37 (3H, t,J=7.6 Hz).

[3742] Step 6.2-[4-(2-ethyl-5-phenyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate

[3743] The title compound was prepared according to the proceduredescribed in Example 3 from2-[4-(2-ethyl-5-phenyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 5).

[3744] MS (ESI) m/z 540 [M+H]⁺, 538 [M−H]⁻.

[3745]¹H-NMR (CDCl₃) δ: 8.00 (1H, s), 7.94 (2H, d, J=8.2 Hz), 7.65 (2H,d, J=8.6 Hz), 7.43-7.48 (3H, m), 7.29-7.36 (7H, m), 7.15 (2H, d, J=8.4Hz), 4.39 (2H, t, J=6.8 Hz), 3.01 (2H, t, J=6.4 Hz), 2.70 (2H, q, J=7.4Hz), 2.43 (s, 3H), 1.35 (3H, t, J=7.6 Hz).

Example 3582-{4-[2-Ethyl-5-(5-pyrimidinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3746] Step 1.2-{4-[2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-1-yl]phenyl)ethanol

[3747] To a solution of2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (Example 357step 4, 2.5 g, 7.24 mmol) and bis(pinacolato)diboron (1.84 g, 7.24 mmol)in DMSO was added KOAc (2.13 g, 21.7 mmol),1,1′-Bis(diphenylphosphino)ferrocene (241.mg, 0.43 mmol) andPd(dppf)Cl₂.CH₂Cl₂ (362 mg, 0.44 mmol). This mixture was stirred at 80°C. for 7 h. The reaction mixture was diluted with water and extractedwith ethyl acetate (3×80 ml). The organic layer was washed with brine,dried (MgSO₄) and concentrated to give black oil. This mixture waspurified by neutral SiO₂ chromatography eluting with hexane/ethylacetate (1:4) to afford 1.38 g (35%) of the title compound as pinksolids.

[3748] MS (EI) m/z 391 [M−H]⁺.

[3749]¹H-NMR (CDCl₃) δ: 8.25 (1H, s), 7.64 (2H, dd, J=O.8, 8.1 Hz), 7.45(2H, d, J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.08 (1H, d, J=8.1 Hz), 3.99(2H, t, J=6.5 Hz), 3.00 (2H, t, J=6.5 Hz), 2.81 (2H, q, J=7.6 Hz), 1.36(12H, s), 1.32 (3H, t, J=7.8 Hz).

[3750] Step 2.2-{4-[2-ethyl-5-(5-pyrimidinyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3751] To a solution of2-{4-[2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 1, 100 mg, 0.26 mmol) and 5-bromopyrimidine (45 mg, 0.28 mmol) in1,2-dimethoxyethane (3.5 ml) was added sat. NaHCO₃ aq. (1.2 ml) andPd(PPh₃)₄ (60 mg, 0.05 mmol). This mixture was stirred at 70° C. for 17h. The reaction mixture was diluted with water and extracted with CH₂Cl₂(3×10 ml). The organic layer was dried (MgSO₄) and concentrated to givelight brown oil. This mixture was purified by SiO₂ preparative TLC(CH₂Cl₂/methanol=10/1) to afford 45 mg (50%) of the title compound.

[3752] MS (EI) m/z 344 (M⁺).

[3753]¹H-NMR (CDCl₃) δ: 9.19 (1H, s), 9.00(2H, s), 7.99 (1H, s), 7.49(2H, d, J=8.2 Hz), 7.31-7.42 (3H, m), 7.23 (1H, d, J=8.4 Hz), 4.00 (2H,q, J=6.1 Hz), 3.02 (2H, t, J=6.4 Hz), 2.83 (2H, q, J=7.6 Hz), 1.39 (3H,t, J=7.6 Hz).

[3754] Step 3.2-{4-[2-ethyl-5-(5-pyrimidinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3755] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[2-ethyl-5-(5-pyrimidinyl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 2).

[3756] MS (ESI) m/z 542 [M+H]⁺, 540 [M−H]⁻.

[3757]¹H-NMR (CDCl₃) δ: 9.20 (1H, s), 8.97 (2H, s), 7.30-7.42 (4H, m),7.24 (2H, d, J=8.2 Hz), 7.14 (2H, d, J=8.2 Hz), 4.41 (2H, t, J=6.4 Hz),3.03 (2H, t, J=6.1 Hz), 2.89 (2H, q, J=7.4 Hz), 2.43 (3H, s), 1.34 (3H,t, J=7.4 Hz).

Example 3592-4-[2-Ethyl-5-(4-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3758] Step 1.2-{4-[2-ethyl-5-(4-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3759] The title compound was prepared according to the proceduredescribed in step 1 of Example 358 from 4-bromopyridine hydrochloride(step 2).

[3760] MS (EI) m/z 343 (M)⁺.

[3761]¹H-NMR (CDCl₃) δ: 8.66 (2H, d, J=6.1 Hz), 8.07 (1H, d, J=1.2 Hz),7.57 (2H, d, J=6.1 Hz), 7.45-7.52 (3H, m), 7.34 (2H, d, J=8.4 Hz), 7.20(1H, d, J=8.4 Hz), 4.00 (2H, br.s), 3.03 (2H, t, J=6.6 Hz), 2.83 (2H, q,J=7.4 Hz), 1.39 (3H, t, J=7.4 Hz).

[3762] Step 2.2-{4-[2-ethyl-5-(4-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3763] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[2-ethyl-5-(4-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethanol (step1).

[3764] MS (ESI) m/z 541 [M+H]⁺, 539 [M−H]⁻.

[3765]¹H-NMR (CDCl₃) δ: 8.52 (2H, d, J=5.8 Hz), 8.00 (1H, s), 7.94 (2H,d, J=8.1 Hz), 7.48 (2H, d, J=5.8 Hz), 7.23-7.40 (5H, m), 7.20 (2H, d,J=8.1 Hz), 7.00 (2H, d, J=8.2 Hz), 4.41 (2H, t, J=5.8 Hz), 3.02 (2H, t,J=5.8 Hz), 2.76 (2H, q, J=7.4 Hz), 2.39 (3H, s), 1.32 (3H, t, J=7.4 Hz).

Example 3602-{4-[2-Ethyl-5-(3-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3766] Step 1.2-{4-[2-ethyl-5-(3-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3767] The title compound was prepared according to the proceduredescribed in step 1 of Example 358 from 3-bromopyridine.

[3768] MS (EI) m/z 343 (M)⁺.

[3769]¹H-NMR (CDCl₃) δ: 8.91 (1H, d, J=1.8 Hz), 8.55-8.61 (1H, m), 8.00(1H, s), 7.90-7.97 (1H, m), 7.48 (2H, d, J=8.2 Hz), 7.42 (1H, d, J=8.7Hz), 7.35 (2H, d, J=8.2 Hz), 7.21 (1H, d, J=8.4 Hz), 4.00 (2H, m), 3.02(2H, t, J=6.5 Hz), 2.83 (2H, q, J=7.6 Hz), 1.92 (1H, s), 1.39 (3H, t,J=7.6 Hz).

[3770] Step 2.2-{4-[2-ethyl-5-(3-pyridin)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3771] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[2-ethyl-5-(3-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethanol (step1).

[3772] MS (ESI) m/z 541 [M+H]⁺, 539 [M−H]⁻.

[3773]¹H-NMR (CDCl₃) δ: 8.76 (1H, s), 8.63 (1H, m), 7.87-8.01 (4H, m),7.22-7.50 (6H, m), 7.23-7.40 (5H, m), 7.16 (2H, d, J=8.2 Hz), 7.00 (1H,d, J=8.2 Hz), 4.42 (2H, br.s), 3.01 (2H, br.s), 2.74 (2H, q, J=7.4 Hz),2.43 (3H, s), 1.31 (3H, t, J=7.4 Hz).

Example 3612-{4-[2-Ethyl-5-(2-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3774] Step 1.2-{4-[2-ethyl-5-(2-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3775] The title compound was prepared according to the proceduredescribed in step 1 of Example 358 from 2-bromopyridine.

[3776] MS (EI) m/z 343 (M)⁺.

[3777]¹H-NMR (CDCl₃) δ: 8.70 (1H, dd, J=1.5, 5.3 Hz), 8.32 (1H, d, J=1.5Hz), 8.00 (1H, dd, J=1.5, 8.4 Hz), 7.76-7.80 (2H, m), 7.48 (2H, d, J=8.2Hz), 7.35 (2H, d, J=8.2 Hz), 7.16-7.23 (2H, m), 3.93-4.05 (2H, m), 3.01(2H, t, J=6.6 Hz), 2.83 (2H, q, J=7.6 Hz), 1.91 (1H, s), 1.38 (3H, t,J=7.6 Hz).

[3778] Step 2.2-4-[2-ethyl-5-(2-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3779] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[2-ethyl-5-(2-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethanol (step1).

[3780] MS (ESI) m/z 541 [M+H]⁺, 539 [M−H]⁻.

[3781]¹H-NMR (CDCl₃) δ: 8.68 (1H, d, J=4.6 Hz), 8.31 (1H, s), 7.88-7.98(3H, m), 7.73-7.82 (2H, m), 7.17-7.26 (5H, m), 7.07-7.17 (3H, m), 4.29(2H, t, J=6.3 Hz), 2.90 (2H, t, J=6.4 Hz), 2.73 (2H, q, J=7.6 Hz), 2.36(3H, s), 1.28 (3H, t, J=7.6 Hz).

Example 3622-{4-[2-Ethyl-5-(4-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3782] Step 1.2-{4-[2-ethyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}ethanol

[3783] The title compound was prepared according to the proceduredescribed in step 1 of Example 358 from 4-bromo-1-methyl-1H-pyrazole(Huettel et al., Liebigs Ann. Chem., 1955, 593, 179).

[3784] MS (EI) m/z 343 (M⁺).

[3785]¹H-NMR (CDCl₃) δ: 7.86 (1H, s), 7.78 (1H, s), 7.46 (2H, d, J=8.4Hz), 7.28-7.35 (3H, m), 7.09 (2H, d, J=8.2 Hz), 3.99 (2H, m), 3.01 (2H,t, J=6.4 Hz), 2.81 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).

[3786] Step 2.2-{4-[2-ethyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3787] The title compound was prepared according to the proceduredescribed in Example 3 from2-{4-[2-ethyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}ethanol(step 1).

[3788] MS(ESI) m/z 544 [M+H]⁺, 542 [M−H]⁻.

[3789]¹H-NMR (CDCl₃) δ: 7.95 (1H, s), 7.92 (1H, s), 7.86 (4H, m), 7.77(1H, s), 7.62 (1H, s), 7.24-7.40 (7H, m), 7.06 (21H, d, J=7.7 Hz), 4.39(2H, t, J=6.0 Hz), 3.97 (3H, s), 3.02 (2H, q, J=6.3 Hz), 2.78 (2H, q,J=7.4 Hz), 2.44 (3H. s), 1.35 (3H, t, J=7.4 Hz).

Example 3632-{4-[6-Chloro-2-[3-oxo-3-(1-pyrrolidinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3790] The title compound was prepared according to the proceduredescribed in Example 339 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (Example 339, step 2) and 4-oxo-4-(1-pyrrolidinyl)butanoic acid(McCasland; Proskow, J. Org. Chem., 1957, 22, 122.).

[3791] m.p.: 98-105° C.

[3792] IR (KBr) v: 2875, 1747, 1624, 1517, 1400, 1346, 1130, 1085 cm⁻¹.

[3793] MS (ESI) m/z: 663 (MH⁺), 661 ([M−H]⁻).

[3794]¹H-NMR (CDCl₃) δ: 8.08 (1H, s), 7.92 (2H, d, J=8.2 Hz), 7.22-7.36(7H, m), 4.38 (2H, t, J=6.6 Hz), 3.49 (2H, t, J=6.8 Hz), 3.43 (2H, t,J=6.8 Hz), 2.97-3.07 (4H, m), 2.88 (2H, m), 2.44 (3H, s), 1.94-1.98 (2H,m), 1.82-1.86 (2H, m).

Example 3642-{4-[6-Chloro-2-[3-oxo-3-(1-piperidinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3795] The title compound was prepared according to the proceduredescribed in Example 339 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (Example 339, step 2) and 4-oxo-4-(1-piperidinyl)butanoic acid(Becker, Frederick F.; Banik, Bimal K., Bioorg. Med. Chem. Lett., 1998,20, 2877).

[3796] m.p.: 210° C.

[3797] IR (KBr) v: 1753, 1649, 1515, 1433, 1406, 1366, 1161, 1118, 1091cm⁻¹.

[3798] MS (ESI) m/z: 677 (MH⁺), 675 ([M−H]⁻).

[3799]¹H-NMR (CDCl₃) δ: 8.14 (1H, s), 7.78 (2H, d, J=8.4 Hz), 7.47-7.56(4H, m), 7.42 (2H, d, J=8.4 Hz), 7.31 (1H, s), 4.29 (2H, t, J=6.6 Hz),3.37-3.40 (4H, m), 2.92-2.99 (6H, m), 2.36 (3H, s), 1.50-1.56 (4H, m),1.35-1.36 (2H, m).

Example 3652-{4-[6-Chloro-2-[3-(2-oxo-1-pyrrolidinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3800] The title compound was prepared according to the proceduredescribed in Example 339 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (Example 339, step 2) and 4-(2-oxo-1-pyrrolidinyl)butanoic acid(Miyano, Seiji; Fujii, Shinichiro; Yamashita, Osamu; Toraishi, Naoko;Sumoto, Kunihiro, J. Heterocycl. Chem., 1982, 19, 1465).

[3801] m.p.: 85-90° C.

[3802] IR (KBr) v: 1745, 1624, 1517, 1433, 1348, 1299, 1161, 1130, 1085cm⁻¹.

[3803] MS (ESD) m/z: 663 (MH⁺), 661 ([M−H]⁻).

[3804]¹H-NMR (CDCl₃) δ: 8.09 (1H, s), 7.91 (2H, d, J=8.5 Hz), 7.19-7.33(7H, m), 4.42 (2H, t, J=6.0 Hz), 3.38 (2H, t, J=7.0 Hz), 3.27 (2H, t,J=7.0 Hz), 3.00 (2H, t, J=6.0 Hz), 2.70-2.75 (2H, m), 2.42 (3H, s),2.37-2.40 (2H, m), 1.93-2.04 (4H, m).

Example 3662-{4-[6-Chloro-2-[3-(2-oxo-1-piperidinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3805] The title compound was prepared according to the proceduredescribed in Example 339 from2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (Example 339, step 2) and 4-(2-oxo-1-piperidinyl)butanoic acid(Miyano, Seiji; Fujii, Shinichiro; Yamashita, Osamu; Toraishi, Naoko;Sumoto, Kunihiro, J. Heterocycl. Chem., 1982, 19, 1465).

[3806] m.p.: 98-105° C.

[3807] IR (KBr) v: 1745, 1618, 1433, 1348, 1301, 1230, 1161, 1130, 1085cm⁻¹.

[3808] MS (ESI) m/z: 677 (MH⁺), 675 ([M−H]⁻).

[3809]¹H-NMR (CDCl₃) δ: 8.08 (1H, s), 7.89 (2H, d, J=8.0 Hz), 7.16-7.29(7H, m), 4.40 (2H, t, J=5.9 Hz), 3.35 (2H, t, J=7.2 Hz), 3.25-3.27 (2H,m), 2.98 (2H, t, J=5.9 Hz), 2.73 (2H, t, J=7.2 Hz), 2.35-2.40 (5H, m),1.92-1.99 (2H, m), 1.73-1.76 (4H, m).

Example 367N-{[(2-{4-[6-Chloro-2-(1-hydroxyethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3810] Step 1.1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol

[3811] The title compound was prepared according to the proceduredescribed in Example 339, step 3 & Example 1, step 5 from4-chloro-N²-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1,2-benzenediamineand lactic acid.

[3812]¹H-NMR (CDCl₃) δ: 8.14 (1H, s), 7.49 (2H, d, J=8.2 Hz), 7.37 (2H,d, J=8.2 Hz), 4.90-4.96 (1H, m), 3.83 (2H, t, J=6.8 Hz), 3.75 (1H, d,H=8.1 Hz), 3.22 (2H, t, J=6.8 Hz), 1.57 (3H, d, J=6.9 Hz).

[3813] Step 2.N-{[(2-{4-[6-chloro-2-(1-hydroxyethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3814] The title compound was prepared according to the proceduredescribed in Example 1 from1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol(step 1).

[3815] m.p.: 220° C.

[3816] IR (KBr) v: 3348, 1706, 1533, 1519, 1434, 1344, 1328, 1126 cm⁻¹.

[3817] MS (ESI) m/z: 581 (MH⁺), 579 ([M−H]⁻).

[3818]¹H-NMR (CDCl₃) δ: 8.23 (1H, s), 7.78 (2H, d, J=8.1 Hz), 7.32-7.50(7H, m), 6.58 (1H, br.s), 5.66 (1H, br.s), 4.78 (1H, br.s), 3.30-3.32(2H, m), 2.79-2.82 (2H, m), 2.34 (3H, s), 1.51 (3H, d, J=6.8 Hz).

Example 368N-{[(2-{4-[2-Acetyl-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3819] Step 1.1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanone

[3820] A solution of1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol(Example 367, step 1, 400 mg, 1 mmol) in CH₂Cl₂ was added MnO₂ (2.7 g,32 mmol). The mixture was stirred at room temperature for 24 h. This wasdirectly purified by flash column chromatography eluting withhexane/ethyl acetate (4:1) to afford 350 mg (88%) of the title compoundas white solids.

[3821]¹H-NMR (CDCl₃) δ: 8.31 (1H, s), 7.44 (2H, d, J=8.1 Hz), 7.23-7.28(3H, m), 3.82 (2H, t, J=7.3 Hz), 3.21 (2H, t, J=7.3 Hz), 2.80 (3H, s).

[3822] Step 2.N-{[(2-{4-[2-acetyl-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3823] The title compound was prepared according to the proceduredescribed in Example 1 from1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanone(step 1)

[3824] m.p.: 225° C.

[3825] IR (KBr) v: 3350, 1697, 1519, 1326, 1294, 1134, 1083 cm⁻¹.

[3826] MS (ESI) m/z: 579 (MH⁺), 577 ([M−H]⁻).

[3827]¹H-NMR (CDCl₃) δ: 8.31 (1H, s), 7.74 (2H, d, J=8.4 Hz), 7.21-7.39(7H, m), 6.70 (1H, br.s), 3.55-3.62 (2H, m), 2.94 (2H, t, J=7.2 Hz),2.81 (3H, s), 2.40 (3H, s).

Example 369N-{[(2-{4-[6-Chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3828] Step 1.2-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]-2-propanol

[3829] The title compound was prepared according to the proceduredescribed in Example 339, step 3 & Example 1, step 5 from2-hydroxyisobutyric acid and4-chloro-N²-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1,2-benzenediamine.

[3830]¹H-NMR (CDCl₃) δ: 8.13 (1H, s), 7.46 (2H, d, J=8.2 Hz), 7.34 (2H,d, J=8.2 Hz), 7.00 (1H, s), 3.84 (2H, t, J=7.0 Hz), 3.38 (1H, s), 3.22(2H, t, J=7.00 Hz), 1.53 (6H, s).

[3831] Step 2.N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3832] The title compound was prepared according to the proceduredescribed in Example 1 from2-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]-2-propanol(step 1).

[3833]¹H-NMR (CDCl₃) δ: 8.13 (1H, s), 7.73 (2H, d, J=8.2 Hz), 7.30-7.39(6H, m), 6.99 (1H, s), 6.68 (1H, br.s), 3.55-3.66 (2H, m), 2.95 (2H, t,J=6.6 Hz), 2.42 (3H, s), 1.13 (6H, d, J=6.2 Hz).

Example 370N-{[(2-{4-[6-Chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamidemono P-toluenesulfonate

[3834] The title compound was prepared according to the proceduredescribed in Example 231 fromN-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(Example 369).

[3835] m.p.: 146-150° C.

[3836] IR (KBr) v: 1685, 1515, 1448, 1340, 1124, 1089, 1010 cm⁻¹.

Example 371N-{1-[6-Chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethyl}acetamide

[3837] Step 1. 1,1-dimethylethyl1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethylcarbamate

[3838] The title compound was prepared according to the proceduredescribed in Example 339, step 3 & Example 1, step 5 fromN-(tert-butoxycarbonyl)-alanine and2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethylacetate (Example 339, step 2).

[3839] MS (EI) m/z: 483 (M⁺).

[3840]¹H-NMR (CDCl₃) δ: 8.12 (1H, s), 7.50 (2H, d, J=8.6 Hz), 7.35-7.37(2H, m), 7.24 (1H, s), 5.46 (1H, br.s), 4.92-4.98 (1H, m), 3.954.02 (2H,m), 3.00 (2H, t, J=6.5 Hz), 1.43 (3H, s), 1.40 (9H, s).

[3841] Step 2. 1,1-dimethylethyl1-[6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethylcarbamate

[3842] The title compound was prepared according to the proceduredescribed in Example 1 from 1,1-dimethylethyl1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethylcarbamate(step 1)

[3843]¹H-NMR (CDCl₃) δ: 8.13 (1H, s), 7.79 (2H, d, J=8.2 Hz), 7.15-7.35(7H, m), 6.50 (1H, br.s), 5.55 (1H, d, J=8.6 Hz), 4.884.93 (1H, m),3.46-3.52 (2H, m), 2.87-2.96 (2H, m), 2.41 (3H, s), 1.40 (12H, s).

[3844] Step 3.N-{[(2-{4-[2-(1-aminoethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3845] A solution of 1,1-dimethylethyl1-[6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethylcarbamate(step 2, 190 mg, 0.28 mmol) in CH₂Cl₂ (2 ml) was added trifluoroaceticacid (1 ml) and stirred at room temperature for 2 h. The mixture wasadded water (10 ml) and extracted with CH₂Cl₂ (20 ml). The organic layerwas washed with brine (10 ml), then dried (Na₂SO₄). After removal ofsolvent, the crude product was purified by flash column chromatographyeluting with CH₂Cl₂/MeOH (10:1/5:1) to afford 160 mg (99%) of the titlecompound as white solids.

[3846] MS (ESI) m/z: 580 (MH⁺), 578 ([M−H]⁻).

[3847] Step 4.N-{1-[6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethyl}acetamide

[3848] A mixture ofN-{[(2-{4-[2-(1-aminoethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(step 3, 100 mg, 0.17 mmol) in CH₂Cl₂ (12 ml) was added acetyl chloride(0.01 ml, 0.18 mmol) and stirred at room temperature for 5 h. Themixture was added water (10 ml) and extracted with CH₂Cl₂ (20 ml). Theorganic layer was washed with brine (10 ml), then dried (Na₂SO₄). Afterremoval of solvent, the crude product was purified by flash columnchromatography eluting with CH₂Cl₂/MeOH (10:1) to afford 59 mg (53%) ofthe title compound as white solids.

[3849] MS (ESI) m/z: 622 (MH⁺), 620 ([M−H]⁻).

[3850]¹H-NMR (CDCl₃) δ: 8.14 (1H, s), 7.80 (2H, d, J=8.2 Hz), 7.25-7.40(7H, m), 7.00 (1H, br.s), 6.03 (1H, br.s), 5.15-5.20 (1H, m), 3.43-3.68(2H, m), 2.88-2.98 (2H, m), 2.39 (3H, s), 1.96 (3H, s), 1.51 (3H, d,J=6.9 Hz).

Example 372N-{1-[6-Chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethyl}acetamidemono P-toluenesulfonate

[3851] The title compound was prepared according to the proceduredescribed in Example 231 fromN-{1-[6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethyl}acetamide(Example 371).

[3852] m.p.: 135-142° C.

[3853] IR (KBr) v: 3267, 1676, 1517, 1456, 1236, 1163, 1122, 1010 cm⁻¹.

Example 3732-{4-[2-Ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3854] Step 1.(3-amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)(phenyl)methanone

[3855] The title compound was prepared according to the proceduredescribed in Example 78 from (4-chloro-3-nitrophenyl)(phenyl)methanone.

[3856]¹H-NMR (CDCl₃) δ: 7.77 (2H, d, J=6.9 Hz), 7.42-7.55 (3H, m), 7.36(1H, s), 7.14-7.25 (4H, m), 6.97 (2H, d, J=8.5 Hz), 5.64 (1H, s),3.83-3.89 (2H, m), 3.64 (2H, br.s), 2.84 (2H, t, J=6.6 Hz), 1.47 (1H,br.s).

[3857] Step 2.{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}(phenyl)methanone

[3858] The title compound was prepared according to the proceduredescribed in Example 1 from(3-amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)(phenyl)methanone(step 1.).

[3859]¹H-NMR (CDCl₃) δ: 8.21 (1H, s), 7.80-7.84 (3H, m), 7.44-7.57 (5H,m), 7.27-7.34 (2H, m), 7.18 (1H, d, J=8.4 Hz), 3.98-4.03 (2H, m), 3.02(2H, t, J=6.3 Hz), 2.81 (2H, q, J=7.6 Hz), 1.89 (1H, t, J=5.4 Hz), 1.37(3H, t, J=7.6 Hz).

[3860] Step 3.2-{4-[2-ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3861] The title compound was prepared according to the proceduredescribed in Example 3 from{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}(phenyl)methanone(step 2).

[3862] MS (ESI) m/z: 568 (MH⁺), 566 ([M−H]⁻).

[3863]¹H-NMR (CDCl₃) δ: 8.21 (1H, s), 7.92 (2H, d, J=8.4 Hz), 7.79-7.84(3H, m), 7.44-7.58 (3H, m), 7.23-7.36 (6H, m), 7.15 (1H, d, J=8.6 Hz),4.37 (2H, t, J=6.6 Hz), 3.01 (2H, t, J=6.6 Hz), 2.79 (2H, q, J=7.6 Hz),2.42 (3H, s), 1.34 (3H, t, J=7.6 Hz).

Example 3742-{4-[2-Ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamatemono P-toluenesulfonate

[3864] The title compound was prepared according to the proceduredescribed in Example 231 from2-{4-[2-ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate (Example 373).

[3865] m.p.: 102-107° C.

[3866] IR (KBr) v: 1747, 1654, 1517, 1448, 1033, 1008 cm⁻¹.

Example 375N-{[(2-4-[2-Ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]phenyl)ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3867] Step 1.N-{[(2-{4-[2-ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

[3868] The title compound was prepared according to the proceduredescribed in Example 78 from{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}(phenyl)methanone(Example 373, step 2).

[3869] MS (ESI) m/z: 567 (MH⁺), 565 ([M−H]⁻).

[3870]¹H-NMR (CDCl₃) δ: 8.20 (1H, s), 7.72-7.83 (5H, m), 7.28-7.60 (9H,m), 7.15 (1H, d, J=8.6 Hz), 6.74 (1H, br.s), 3.59 (2H, m), 2.94 (2H, t,J=7.1 Hz), 2.82 (2H, q, J=7.4 Hz), 2.39 (3H, s), 1.35 (3H, t, J=7.4 Hz).

Example 376N-{[(2-{4-[2-Ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamidemono P-toluenesulfonate

[3871] The title compound was prepared according to the proceduredescribed in Example 231 fromN-{[(2-{4-[2-ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(Example 375).

[3872] m.p.: 198° C.

[3873] IR (KBr) v: 1697, 1660, 1596, 1519, 1446, 1319, 1035 cm⁻¹.

Example 3772-{4-[2-[1-(Acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3874] Step 1.2-{4-[6-chloro-2-(1-chloro-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylacetate

[3875] To a solution of2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylacetate (300 mg, 0.68 mmol) in dichloromethane (15 ml) was added thionylchloride (0.07 ml, 1.02 mmol) and the reaction mixture was refluxedovernight. The reaction mixture was poured into water (10 ml) and themixture was extracted with dichloromethane (30 ml). The organic layerwas washed with brine (10 ml), then dried (Na₂SO₄). The solvent wasremoved to give 273 mg (87%) of the title compound as white amorphous.

[3876] MS (EI) m/z: 458 (M⁺).

[3877] Step 2.2-{4-[2-(1-azido-1-methylethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylacetate

[3878] A mixture of2-{4-[6-chloro-2-(1-chloro-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylacetate (step 1, 273 mg, 0.68 mmol), sodium azide (88 mg, 1.36 mmol), KI(112 mg, 0.68 mmol) in DMF (8 ml) was stirred under nitrogen at roomtemperature for 5.5 h. The reaction mixture was poured into water (5 ml)and the aqueous mixture was extracted with ethyl acetate(30 ml). Theorganic layer was washed with water (5 ml) and brine (10 ml), then dried(Na₂SO₄). After removal of solvent, the crude product was purified byflash column chromatography eluting with hexane/ethyl acetate (2/1) toafford 133 mg (42%) of the title compound as yellow oil.

[3879] MS (EI) m/z: 465 (M⁺).

[3880]¹H-NMR (CDCl₃) δ: 8.17 (1H, s), 7.46 (2H, d, J=8.4 Hz), 7.35 (2H,d, J=8.4 Hz), 7.02 (1H, s), 4.39 (2H, t, J=7.0 Hz), 3.09 (2H, t, J=7.0Hz), 2.08 (3H, s), 1.70 (6H, s).

[3881] Step 3.2-{4-[2-(1-amino-1-methylethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylacetate

[3882] A mixture of2-{4-[2-(1-azido-1-methylethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylacetate (step 2, 133 mg, 0.28 mmol) and Lindlar catalyst (13 mg) inmethanol (5 ml) was stirred under H₂ atmosphere at room temperature for2.5 h. The catalyst was removed by filtration through a pad of celiteand the filtrates were concentrated to give the title compound as yellowoil (121 mg, 98%).

[3883] MS (EI) m/z: 439 (M⁺).

[3884] Step 4.2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylacetate

[3885] To a solution of2-{4-[2-(1-amino-1-methylethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylacetate (step 3, 121 mg, 0.27 mmol) in dichloromethane (5 ml) was addedacetyl chloride (0.02 ml, 0.3 mmol). The reaction mixture was stirred atroom temperature for 7 h. To the reaction mixture was added water (5 ml)and the aqueous mixture was extracted with dichloromethane (30 ml). Theorganic layer was washed with water (5 ml) and brine (10 ml), then dried(Na₂SO₄). After removal of solvent, the crude product was purified byflash column chromatography eluting with CH₂Cl₂/methanol (10/1) toafford 76 mg (57%) of the title compound as white amorphous.

[3886] MS (EI) m/z: 481 (M⁺).

[3887]¹H-NMR (CDCl₃) δ: 8.14 (1H, s), 7.42 (2H, d, J=8.2 Hz), 7.28 (2H,d, J=8.4 Hz), 6.91 (1H, s), 4.38 (2H, t, J=6.6 Hz), 3.07 (2H, t, J=6.6Hz), 2.06 (3H, s), 1.75 (6H, s), 1.68 (3H, s).

[3888] Step 5.N-{1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1-methylethyl}acetamide

[3889] The title compound was prepared according to the proceduredescribed in step 6 of Example 12-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylacetate(step 4).

[3890]¹H-NMR (CDCl₃) δ: 8.13 (1H, s), 7.44 (2H, d, J=8.4 Hz), 7.27 (2H,d, J=8.4 Hz), 6.92 (1H, s), 5.95 (1H, br.s), 3.98 (2H, t, J=6.4 Hz),2.99 (2H, t, J=6.4 Hz), 1.68-1.75 (9H, m).

[3891] Step 6.2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate

[3892] The title compound was prepared according to the proceduredescribed in Example 3 fromN-{1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1-methylethyl}acetamide(step 5).

[3893] MS (ESI) m/z: 637 (MH⁺), 635 ([M−H]⁻).

[3894]¹H-NMR (CD₃OD) δ: 8.04 (1H, s), 7.83 (2H, d, J=8.4 Hz), 7.45 (2H,d, J=8.4 Hz), 7.34 (2H, d, J=8.5 Hz), 7.26 (2H, d, J=8.5 Hz), 6.93 (1H,s), 4.32 (2H, t, J=6.4 Hz), 3.02 (2H, t, J=6.4 Hz), 2.37 (3H, s), 1.75(6H, s), 1.53 (3H, s).

Example 3782-{4-[2-[1-(Acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamateP-toluenesulfonate

[3895] The title compound was prepared according to the proceduredescribed in Example 231 fromN-{[(2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide(Example 377)

[3896] IR (KBr) v: 1751, 1508, 1450, 1340, 1161, 1122 cm⁻¹.

Example 3796-Chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

[3897] Step 1.2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethylmethanesulfonate

[3898] A mixture of6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide(Example 111, step 4, 500 mg, 1.45 mmol), triethylamine (293 mg, 2.90mmol) and methansulfonyl chloride (322 mg, 2.9 mmol) in dichloromethane(20 ml) was stirred at room temperature for 6 h. The reaction mixturewas poured into water, and extracted with dichloromethane (50 ml). Theorganic layer was washed with brine (50 ml), then dried (Na₂SO₄). Afterremoval of solvent, the crude product was purified by TLC withhexane/ethyl acetate (1:1) to afford 304 mg (50%) of the title compoundas white solids.

[3899] MS (ESI) m/z: 422 ([M+H]⁺).

[3900]¹H-NMR (CDCl₃) δ: 7.54 (1H, s), 7.44 (2H, d, J=8.3 Hz), 7.29 (2H,d, J=8.3 Hz), 7.13 (1H, s), 3.82 (2H, t, J=7.0 Hz), 3.19 (2H, t, J=7.0Hz), 2.82 (6H, s), 2.75 (2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.6 Hz).

[3901] Step 2.6-chloro-2-ethyl-1-{4-[2-(methylamino)ethyl]phenyl}-1H-benzimidazole-5-carboxamide

[3902] A mixture of2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethylmethanesulfonate (step 1, 304 mg, 0.72 mmol), a solution of methyl amine(40% in methanol, 10 ml) and water (5 ml) in a sealed tube was heatedovernight at 100° C. The reaction mixture was partitioned betweendichloromethane (30 ml) and water (30 ml). The organic phase wasseparated and the aqueous phase was extracted with dichloromethane (50ml). The combined organic phases were washed with brine (50 ml) anddried (Na₂SO₄). After removal of solvent, the crude product was purifiedby TLC with dichloromethane/methanol (10:1) to afford 154 mg (60%) ofthe title compound as yellow solids.

[3903]¹H-NMR (CDCl₃) δ: 7.54 (1H, s), 7.43 (2H, d, J=8.2 Hz), 7.29 (2H,d, J=8.2 Hz), 7.12 (1H, s), 3.62 (2H, t, J=7.0 Hz), 3.01 (2H, t, J=7.0Hz), 2.82 (6H, s), 2.75 (2H, q, J=7.6 Hz), 1.34 (2H, t, J=7.6 Hz).

[3904] Step 3.6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

[3905] The reaction was carried out according to the procedure describedin step 10 of Example 1 from6-chloro-2-ethyl-1-{4-[2-(methylamino)ethyl]phenyl}-1H-benzimidazole-5-carboxamide(step 2).

[3906] MS (ESI) m/z: 554 (MH⁺), 552 ([M−H]⁻).

[3907]¹H-NMR (CDCl₃) δ: 8.09 (1H, s), 7.97-7.94 (2H, d, J=8.4 Hz),7.40-7.31 (4H, m), 7.16-7.13 (2H, d, J=8.4 Hz), 7.07 (1H, s), 6.36 (1H,br), 3.52 (2H, br), 2.98 (2H, br), 2.93 (3H, s), 2.78-2.69 (2H, d, J=7.6Hz), 2.42 (3H, s), 1.34-1.28 (3H, t, J=7.6 Hz).

Example 3806-Chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamidesodium salt

[3908] The title compound was prepared according to the proceduredescribed in Example 2 from6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide(Example 379).

[3909] MS (ESI) m/z: 554 (MH⁺), 552 ([M−H]⁻).

1. A compound of the following formula:

or the pharmaceutically acceptable salts thereof, wherein Y¹, Y², Y³ andY⁴ are independently selected from N, CH or C(L); R¹ is H, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy,halo-substituted C₁₋₈ alkoxy, C₁₋₈ alkyl-S(O)m-, Q¹—, pyrrolidinyl,piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C₁₋₈alkyl)amino, C₁₋₄alkyl-C(═O)—N(R³)— or C₁₋₄alkyl-S(O)m-N(R³)—, whereinsaid C₁₋₈ alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl are optionallysubstituted with halo, C₁₋₃ alkyl, hydroxy, oxo, C₁₋₄ alkoxy-, C₁₋₄alkyl-S(O)m-, C₃₋₇ cycloalkyl-, cyano, indanyl,1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl,oxopyrrolidinyl, oxopiperidyl, Q¹—, Q¹—C(═O)—Q¹—O—, Q¹—S(O)m-,Q¹—C₁₋₄alkyl-O—, Q¹—C₁₋₄alkyl-S(O)m-, Q¹—C₁₋₄alkyl-C(O)—N(R³)—,Q¹—C₁₋₄alkyl-N(R³)— or C₁₋₄alkyl-C(O)—N(R³)—; Q¹ is a 5-12 memberedmonocyclic or bicyclic aromatic ring optionally containing up to 4heteroatoms selected from O, N and S, and is optionally substituted withhalo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, nitro, amino, mono- ordi-(C₁₋₄alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O)—, HO(O═)C—,C₁₋₄alkyl-O(O═)C—, R³N(R⁴)C(═O)—, C₁₋₄ alkylsulfonylamino, C₃₋₇cycloalkyl, R³C(═O)N(R⁴)— or NH₂(HN═)C—; A is a 5-6 membered monocyclicaromatic ring optionally containing up to 3 heteroatoms selected from O,N and S, wherein said 5-6 membered monocyclic aromatic ring isoptionally substituted with up to 3 substituents selected from halo,C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, amino, mono- ordi-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, acetyl, R³N(R⁴)C(═O)—, HO(O═)C—,C₁₋₄alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl,R³C(═O)N(R⁴)— and NH₂(HN═)C—; B is halo-substituted C₁₋₆ alkylene, C₃₋₇cycloalkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, —O—C₁₋₅ alkylene, C₁₋₂alkylene-O—C₁₋₂ alkylene or C₁₋₆ alkylene optionally substituted with anoxo group or C₁₋₃ alkyl; W is NH, N—C₁₋₄ alkyl, O, S, N—OR⁵ or acovalent bond; R² is H, C₁₋₄ alkyl, OH or C₁₋₄ alkoxy; Z is a 5-12membered monocyclic or bicyclic aromatic ring optionally containing upto 3 heteroatoms selected from O, N and S, wherein said 5-12 memberedmonocyclic or bicyclic aromatic ring is optionally substituted withhalo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄alkynyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,C₁₋₄alkylC(═O)—, R³C(═O)N(R⁴)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, NH₂(HN═)C—, Q²—S(O)m-, Q²—O—,Q²—N(R³)— or Q²—; L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl,hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,nitro, amino, mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O)—,HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl,R³C(═O)N(R⁴)—, NH₂(HN═)C—, R³N(R⁴)C(═O)—, R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—,Q²—O—, Q²—C₁₋₄alkyl-O—, or two adjacent L groups are optionally joinedtogether to form an alkylene chain having 3 or 4 members in which one ortwo (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;m is 0, 1 or 2; R³ and R⁴ are independently selected from H and C₁₋₄alkyl; R⁵ is H, C₁₋₄ alkyl, C₁₋₄ alkyl-(O═)C— or C₁₋₄ alkyl-O—(O═)C—;and Q² is a 5-12 membered monocyclic or bicyclic aromatic ring, or a5-12 membered tricyclic ring optionally containing up to 3 heteroatomsselected from O, N and S, wherein said 5-12 membered monocyclic orbicyclic aromatic ring is optionally substituted with halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, nitro, amino,mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkyl-(O═)C—,R³(R⁴)C(═O)N—, HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino,C₃₋₇ cycloalkyl, C₁₋₄ alkyl-C(═O)NH— or NH₂(HN═)C—.
 2. A compoundaccording to claim 1, wherein Y¹, Y², Y³, and Y⁴ are independentlyselected from N, CH and C(L); R¹ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, halo-substituted C₁₋₈ alkoxy,C₁₋₈ alkyl-S(O)m-, Q¹—, pyrrolidinyl, piperidyl, oxopyrrolidinyl,oxopiperidyl, amino, mono- or di-(C₁₋₈ alkyl)amino,C₁₋₄alkyl-C(═O)—N(R³)— or C₁₋₄alkyl-S(O)m-N(R³)—, wherein said C₁₋₈alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl are optionally substituted withhalo, C₁₋₃ alkyl, hydroxy, oxo, C₁₋₄ alkoxy-, C₁₋₄ alkyl-S(O)m-, C₃₋₇cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl,1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl,oxopiperidyl, Q¹—, Q¹—C(═O)—, Q¹—O—, Q¹—S(O)m-, Q¹—C₁₋₄ alkyl-O—,Q¹—C₁₋₄ alkyl-S(O)m-, Q¹—C₁₋₄alkyl-C(═O)—N(R³)—, orC₁₋₄alkyl-C(═O)—N(R³)—; Q¹ is a 5-12 membered monocyclic or bicyclicaromatic ring optionally containing up to 4 heteroatoms selected from O,N and S, and is optionally substituted with halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄ alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino,cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl,aminosulfonyl, C₁₋₄ alkylC(═O)—, HO(O═)C—, C₁₋₄ alkyl-O(O)C—,R³N(R⁴)C(═O)—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)—or NH₂(HN═)C—; A is a 5-6 membered monocyclic aromatic ring optionallycontaining up to 2 heteroatoms selected from O, N, and S, wherein said5-6 membered monocyclic aromatic ring is optionally substituted with upto 2 substituents selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy and halo-substituted C₁₋₄ alkoxy; B is C₃₋₇cycloalkylene or C₁₋₆ alkylene optionally substituted with an oxo groupor C₁₋₃ alkyl; W is NH, N—C₁₋₄ alkyl, O or N—OH; R² is H or C₁₋₄ alkyl;Z is a 5-12 membered monocyclic or bicyclic aromatic ring optionallycontaining up to 3 heteroatoms selected from, N and S, wherein said 5-12membered monocyclic or bicyclic aromatic ring is optionally substitutedwith halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl,hydroxy, C₁₋₄ alkoxy, nitro, amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, C₁₋₄ alkylC(═O)—, R³C(═O)N(R⁴)—, HO(O═)C—,C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₁₋₄ alkyl-C(═O)NH—,Q²—S(O)m-, Q²—O—, Q²—N(R³)— or Q²—; L is halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, mono- or di-(C₁₋₄alkyl)amino, halo-substituted C₁₋₄ alkoxy, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄ alkylC(═O)—,HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl,R³C(═O)N(R⁴)—, R³N(R⁴)C(═O)—, R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—, Q²—O—,Q²—C₁₋₄alkyl-O—, or two adjacent L groups are optionally joined togetherto form an alkylene chain having 3 or 4 members in which one or two(non-adjacent) carbon atoms are optionally replaced by oxygen atoms; mis 0 or 2; R³ and R⁴ are independently selected from H and C₁₋₄ alkyl;and Q² is a 5-12 membered monocyclic or bicyclic aromatic ring, or a8-12 membered tricyclic ring optionally containing up to 3 heteroatomsselected from O, N and S, wherein said 5-12 membered monocyclic orbicyclic aromatic ring is optionally substituted with halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, hydroxy, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, mono- or di-(C₁₋₄alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, C₁₋₄ alkyl-(O═)C—, R³(R⁴)C(═O)N—,HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkylor C₁₋₄ alkyl-C(═O)NH—.
 3. A compound according to claim 2, wherein Y¹,Y², Y³, and Y⁴ are independently selected from N, CH and C(L); R¹ is H,C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkyl, Q¹—,pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- ordi-(C₁₋₈ alkyl)amino, wherein said C₁₋₈ alkyl is optionally substitutedwith halo, C¹⁻³ alkyl, hydroxy, oxo, C₁₋₄ alkoxy-, C₁₋₄ alkyl-S(O)m-,C₃₋₇ cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl,oxopyrrolidinyl, oxopiperidyl, Q¹—, Q¹—C(O)—, Q¹—O—, Q¹—S—, Q¹—C₁₋₄alkyl-O—, or C₁₋₄alkyl-C(O)—N(R³)—; Q¹ is a 5-12 membered monocyclicaromatic ring optionally containing up to 4 heteroatoms selected from Nand S, and is optionally substituted with halo, C₁₋₄ alkyl, C₁₋₄alkylsulfonyl and C₁₋₄ alkylC(═O)—; A is 5-6 membered monocyclicaromatic ring optionally substituted with halo, C₁₋₄ alkyl or C₁₋₄alkoxy; B is C₃₋₇ cycloalkylene or C₁₋₆ alkylene optionally substitutedwith an oxo group or C₁₋₃ alkyl; W is NH, N—C₁₋₄ alkyl, O or N—OH; R² isH or C₁₋₄ alkyl; Z is 5-12 membered monocyclic or bicyclic aromatic ringoptionally containing up to 3 heteroatoms selected from, N and S,wherein said 5-12 membered monocyclic or bicyclic aromatic ring isoptionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, C₁₋₄ alkenyl, C₁₋₄ alkoxy, nitro, amino, cyano, R³C(═O)N(R⁴)—,C₁₋₄ alkyl-O(O═)C—, Q²—S(O)m-, Q²—O—, Q²—N(R³)— or Q²—; L is halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, mono- or di-(C₁₋₄ alkyl)amino, cyano,HO—C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄ alkylC(═O)—,HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl,R³C(═O)N(R⁴)—, R³N(R⁴)C(═O)—, R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—, Q²—O—,Q²—C₁₋₄alkyl-O—, or two adjacent L groups are optionally joined togetherto form an alkylene chain having 3 or 4 members in which one or two(non-adjacent) carbon atoms are optionally replaced by oxygen atoms; mis 0 or 2; R³ and R⁴ are independently selected from H and C₁₋₄ alkyl;and Q² is a 5 or 6 membered monocyclic aromatic ring, or a 8-12 membered tricyclic ring containing up to 3 heteroatoms selected from N an d S,wherein said 5 or 6 membered monocyclic aromatic ring is o ptionallysubstituted with halo.
 4. A compound according to claim 3, wherein Y¹,Y², Y³ and Y⁴ are independently selected from N, CH and C(L); R¹ is H,C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl or C₃₋₇ cycloalkyl, wherein saidC₁₋₈ alkyl is optionally substituted with halo, C₁₋₃ alkyl, hydroxy,oxo, C₁₋₄ alkoxy-, C₁₋₄ alkyl-S(O)m-, C₃₋₇ cycloalkyl-, cyano, indanyl,pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q¹—, Q¹—C(═O)—,Q¹—O—, Q¹—S—, Q¹—C₁₋₄ alkyl-O—, or C₁₋₄alkyl-C(O)—N(R³)—; Q¹ is a 5 or 6membered monocyclic aromatic ring optionally containing up to 4heteroatoms selected from N and S; A is 5-6 membered monocyclic aromaticring system optionally substituted with halo or C₁₋₄ alkyl; B is or C₃₋₇cycloalkylene or C₁₋₆ alkylene optionally substituted with an oxo groupor C₁₋₃ alkyl; W is NH, N—C₁₋₄ alkyl, O or N—OH; R² is H or C₁₋₄ alkyl;Z is 5-12 membered monocyclic or bicyclic aromatic ring optionallycontaining up to 3 heteroatoms selected from N and S, wherein said 5-12membered monocyclic or bicyclic aromatic ring is optionally substitutedwith halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄alkoxy, nitro, amino, cyano, R³C(═O)N(R⁴)—, C₁₋₄ alkyl-O(O═)C—,Q²—S(O)m-, Q²—O—, Q²—N(R³)— or Q²—; L is halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O), HO(O═)C—, C₁₋₄ alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇cycloalkyl, R³C(═O)NR⁴—, R³N(R⁴)C(═O)—, R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—,Q²—O—, Q²—C₁₋₄alkyl-O—, or two adjacent L groups are optionally joinedtogether to form an alkylene chain having 3 or 4 members in which one ortwo (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;m is 0 or 2; R³ and R⁴ are independently selected from H and C₁₋₄ alkyl;and Q² is 5 or 6 membered monocyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing 1 sulfur atom wherein said 5 or 6membered monocyclic aromatic ring is optionally substituted wi th halo.5. A compound according to claim 4, wherein Y¹, Y², Y³ and Y⁴ areindependently selected from N, CH and C(L); R¹ is C₁₋₅ alkyl or C₃₋₇cycloalkyl, wherein said C₁₋₅ alkyl is optionally substituted with C₁₋₃alkyl, hydroxy, oxo, pyrrolidinyl, piperidyl, oxopyrrolidinyl,oxopiperidyl, Q¹—, or C₁₋₄alkyl-C(O)—N(H)—; Q¹ is 5-12 memberedmonocyclic aromatic ring system optionally containing up to 2heteroatoms selected from N and S, A is 5-6 membered monocyclic aromaticring system; B is C₁₋₃ alkylene optionally substituted with C₁₋₃ alkyl;W is NH, N—C₁₋₂ alkyl or O; R² is H; Z is 5-12 membered monocyclic orbicyclic aromatic ring optionally containing up to 3 heteroatomsselected from N and S, wherein said 5-12 membered monocyclic aromaticring is optionally substituted with halo, C₁₋₄ alkyl, nitro,R³C(═O)N(R⁴)— or Q²—; L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, cyano,HO—C₁₋₄ alkyl, acetyl, R³N(R⁴)C(═O)—, R³N(R⁴)S(O)m-, Q²—, Q²—C(═O)—, ortwo adjacent L groups are joined together to form a methylenedioxygroup; R³ and R⁴ are independently selected from H and C₁₋₄ alkyl; andQ² is 5 or 6 membered monocyclic aromatic ring system.
 6. A compoundaccording to claim 5, wherein Y¹, Y², Y³ and Y⁴ are independentlyselected from N, CH and C—L; R¹ is C₁₋₅ alkyl optionally substitutedwith C₁₋₃ alkyl, hydroxy, oxo, 5 or 6 membered monocyclic aromatic ring,wherein said 5 or 6 membered monocyclic aromatic ring is containing 1 or2 heteroatoms selected from N and S, or C₁₋₄alkyl-C(O)—N(R³)—; A isphenyl; B is C₁₋₂ alkylene optionally substituted with methyl; W is NH,N—CH₃ or O; R² is H; Z is 5-10 membered monocyclic or bicyclic aromaticring optionally containing up to 3 heteroatoms selected from N and S,wherein said 5-10 membered monocyclic aromatic ring is optionallysubstituted with chloro, bromo, methyl, nitro, CH₃C(═O)NH—, tBuC(═O)NH—or phenyl; and L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy,cyano, acetyl, —C(═O)NH₂, trifuluoromethyloxy, methanesulfonyl, or1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined togetherto form a methylenedioxy group.
 7. A compound according to claim 6,wherein Y¹, Y², Y³ and Y⁴ are independently selected from N, CH and C—L;R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl,thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl, or1-acetylamino-1-methylethyl; A is phenyl; B is ethylene or propylene; Wis NH, N—CH₃ or O; R² is H; Z is phenyl, pyrazolyl, thiazolyl,thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl,thiazolyl, thiadiazolyl and thienyl being optionally substituted withone to three substituents independently selected from chloro, bromo,methyl, acetylamino, pivaloylamino, nitro and phenyl; and L is chloro,methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, —C(═O)NH₂,trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, ortwo adjacent L groups are joined together to form a methylenedioxygroup.
 8. A compound according to claim 7, wherein Y¹, Y², Y³ and Y⁴ areselected from the group consisting of a) Y¹ and Y³ are C(L), Y² is CHand Y⁴ is N; b) Y¹ is CH, Y² and Y³ are C(L) and Y⁴ is N; c) Y¹, Y² andY³ are C(L) and Y⁴ is N; d) Y¹ and Y³ are C(L), Y² is N and Y⁴ is CH; e)Y¹ is C(L) and Y², Y³and Y⁴ are CH; f) Y¹, Y³and Y⁴ are CH, and Y² isC(L); g) Y¹, Y² and Y³ are CH, and Y⁴ is C(L); h) Y¹ and Y² are C(L),and Y³ and Y⁴ are CH; i) Y¹ and Y³ are C(L), and Y² and Y⁴ are CH; j) Y¹and Y⁴ are CH, and Y² and Y³ are C(L); k) Y¹ and Y² are CH, Y³ is C(L)and Y⁴ is N; l) Y¹ and Y³ are CH, Y² is C(L) and Y⁴ is N; m) Y¹, Y², Y³and Y⁴ are CH; n) Y¹ and Y² are C(L), Y³ is CH and Y⁴ is N; o) Y¹, Y²and Y⁴ are CH, and Y³ is C(L); p) Y¹ and Y² are C(L), Y³ is N and Y⁴ isCH; q) Y¹ and Y³ are C(L), and Y² and Y⁴ are N; r) Y¹ is C(L), Y² and Y³are CH, and Y⁴ is N; and s) Y² is C(L), Y¹ and Y³ are CH, and Y⁴ is N;R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl,thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl, or1-acetylamino-1-methylethyl; A is phenyl; B is ethylene or propylene; Wis NH, N—CH₃ or O; R² is H; Z is phenyl, pyrazolyl, thiazolyl,thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl,thiazolyl, thiadiazolyl and thienyl being optionally substituted withone to three substituents independently selected from chloro, bromo,methyl, acetylamino, pivaloylamino, nitro and phenyl; and L is chloro,methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, —C(═O)NH₂,trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, ortwo adjacent L groups are joined together to form a methylenedioxygroup.
 9. A compound according to claim 8, wherein Y¹, Y², Y³ and Y⁴ areselected from the group consisting of a) Y¹ and Y³ are C(L), Y² is CHand Y⁴ is N; b) Y¹ is CH, Y² and Y³ are C(L) and Y⁴ is N; c) Y¹, Y² andY³ are C(L) and Y⁴ is N; d) Y¹ and Y³ are C(L), Y² is N and Y⁴ is CH; e)Y¹ is C(L) and Y², Y³and Y⁴ are CH; f) Y¹, Y³ and Y⁴ are CH, and Y² isC(L); g) Y¹, Y² and Y³ are CH, and Y⁴ is C(L); h) Y¹ and Y² are C(L),and Y³ and Y⁴ are CH; i) Y¹ and Y³ are C(L), and Y² and Y⁴ are CH; andj) Y¹ and Y⁴ are CH, and Y² and Y³ are C(L); R¹ is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethylmethylamino, dimethylamino, pyrrolidinyl, pyridyl, or1-acetylamino-1-methylethyl; A is phenyl; B is ethylene or propylene; Wis NH, N—CH₃ or O; R² is H; Z is phenyl, pyrazolyl, thiazolyl,thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl,thiazolyl, thiadiazolyl and thienyl being optionally substituted withone to three substituents independently selected from chloro, bromo,methyl, acetylamino, pivaloylamino, nitro and phenyl; and L is chloro,methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, —C(═O)NH₂,trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, ortwo adjacent L groups are joined together to form a methylenedioxygroup.
 10. A compound according to claim 1 selected from3-(4-{2-[({[(5-chloro-1,3-dimethyl-1h-pyrazol-4-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;3-(4-{2-[({[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;N-[5-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)-1,3,4-thiadiazol-2-yl]acetamide;6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole;6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;2-ethyl-5,7-dimethyl-3-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]propyl}phenyl)-3H-imidazo[4,5-b]pyridine;2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate;5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-propyl-3H-imidazo[4,5-b]pyridine;2-isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;2-butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;2-isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-neopentyl-3H-imidazo[4,5-b]pyridine;5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine;3-{4-[2-({[(4-biphenylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;2-ethyl-5,7-dimethyl-3-{4-[2-({[(1-naphthylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-3H-imidazo[4,5-b]pyridine;2-ethyl-5,7-dimethyl-3-{4-[2-({[(2-naphthylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-3H-imidazo[4,5-b]pyridine;2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;3-(4-{2-[({[(4,5-dichloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;3-{4-[2-({[(1-benzothien-2-ylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;5,6-dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;5-chloro-2-ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;6-cyano-2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine;4-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;7-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;2-ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;4,6-dimethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;5,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;5,6-dichloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl-(4-methylphenyl)sulfonylcarbamate;6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamate;5-chloro-6-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;2-ethyl-3-{4-[2-({[({3-[hydroxy(oxido)amino]phenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;3-(4-{2-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;n-[4-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)phenyl]-2,2-dimethylpropanamide;3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;3-(4-{2-[({[(3-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;3-(4-{2-[({[(5-bromo-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;3-(4-{2-[({[(2-bromophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;3-{4-[2-({[({4-chloro-3-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;N-{[(2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(2-chlorophenyl)sulfonylcarbamate;2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-methyl-2-pyridinyl)sulfonylcarbamate;2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamqate;2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;N-{[(2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-2-thiophenesulfonamide;2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonylcarbamate;2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridine-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate;2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridine-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;and salts thereof.
 11. A compound according to claim 1 selected from6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole;6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate;5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine;2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;5,6-dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine;5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;2-ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamate;6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;N-{[(2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(2-chlorophenyl)sulfonylcarbamate;2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-methyl-2-pyridinyl)sulfonylcarbamate;2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;N-{[(2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-2-thiophenesulfonamide;2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonylcarbamate;2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate;2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridine-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;and salts thereof.
 12. A pharmaceutical composition for the treatment ofa disorder or condition mediated by prostaglandin in a mammal includinga human, which comprises an effective amount of a compound of claim 1,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 13. A method for the treatment of a medicalcondition in which prostaglandins are implicated as pathogens, in amammalian subject including a human, comprising administering to amammal in need of such treatment an effective amount of a compound ofclaim 1 and a pharmaceutically acceptable carrier.
 14. A pharmaceuticalformulation comprising a compound of claim 1, a pharmaceuticallyacceptable carrier and, optionally, one or more other pharmacologicallyactive ingredients.
 15. A compound of the following formula:

or salts thereof wherein Y¹, Y², Y³ and Y⁴ are independently selectedfrom N, CH or C(L); R¹ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, halo-substituted C₁₋₈ alkoxy, C₁₋₈alkyl-S(O)m-, Q¹—, amino, mono- or di-(C₁₋₈ alkyl)amino,C₁₋₄alkyl-C(═O)—N(R³)— or C₁₋₄alkyl-S(O)m-N(R³)—, wherein said C₁₋₈alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl are optionally substituted withhalo, C₁₋₃ alkyl, C₁₋₄ alkoxy-, C₁₋₄ alkyl-S(O)m-, C₃₋₇ cycloalkyl-,cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, Q¹—,Q¹—C(═O)—, Q¹—O—, Q¹—S(O)m-, Q¹—C₁₋₄alkyl-O—, Q¹—C₁₋₄alkyl-S(O)m-,Q¹—C₁₋₄alkyl-C(O)—N(R³)—, Q¹—C₁₋₄alkyl-N(R³)— or C₁₋₄alkyl-C(O)—N(R³)—;Q¹ is a 5-12 membered monocyclic or bicyclic aromatic ring optionallycontaining up to 4 heteroatoms selected from O, N and S, and isoptionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄alkyl)amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,C₁₋₄alkylC(═O)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, R³N(R⁴)C(═O)—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— or NH₂(HN═)C—; A is abenzene ring optionally substituted with up to 3 substituents orpyridine ring optionally substituted with up to 3 substituents, whereinsaid substituents selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy,C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino, cyano,HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,acetyl, R³N(R⁴)C(═O)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— and NH₂(HN═)C—; B isC₂₋₆ alkylene, C₃₋₇ cycloalkylene, C₂₋₆ alkenylene, or C₂₋₆ alkynyleneoptionally substituted with C₁₋₃ alkyl; W is NH or O; P is H, aprotecting group, or Q³—OC(═O)—; Q³ is a 6-10 membered monocyclic orbicyclic aromatic ring optionally substituted with halo, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkylthio, nitro, cyano, C₁₋₄ alkylsulfonyl,C₁₋₄alkylC(═O)—, HO(O═)C—, or C₁₋₄alkyl-O(O═)C—; L is halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄ alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino,cyano, HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl,aminosulfonyl, C₁₋₄alkylC(═O)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)—, NH₂(HN═)C—,R³N(R⁴)C(═O)— or R³N(R⁴)S(O)m-, or two adjacent L groups are optionallyjoined together to form an alkylene chain having 3 or 4 members in whichone or two (non-adjacent) carbon atoms are optionally replaced by oxygenatoms; m is 0, 1 or 2; and R³ and R⁴ are independently selected from Hand C₁₋₄ alkyl.
 16. A compound of the following formula:

or salts thereof wherein Y¹, Y², Y³ and Y⁴ are independently selectedfrom N, CH or C(L); R¹ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, halo-substituted C₁₋₈ alkoxy, C₁₋₈alkyl-S(O)m-, Q¹—, amino, mono- or di-(C₁₋₈ alkyl)amino,C₁₋₄alkyl-C(═O)—N(R³)— or C₁₋₄alkyl-S(O)m-N(R³)—, wherein said C₁₋₈alkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl are optionally substituted withhalo, C₁₋₃ alkyl, C₁₋₄ alkoxy-, C₁₋₄ alkyl-S(O)m-, C₃₋₇ cycloalkyl-,cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, Q¹—,Q¹—C(═O)—, Q¹—O—, Q¹—S(O)m-, Q¹—C₁₋₄alkyl-O—, Q¹—C₁₋₄alkyl-S(O)m-,Q¹—C₁₋₄alkyl-C(O)—N(R³)—, Q¹—C₁₋₄alkyl-N(R³)— or C₁₋₄alkyl-C(O)—N(R³)—;Q¹ is a 5-12 membered monocyclic or bicyclic aromatic ring optionallycontaining up to 4 heteroatoms selected from O, N and S, and isoptionally substituted with halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄alkyl)amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,C₁₋₄alkylC(═O)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, R³N(R⁴)C(═O)—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— or NH₂(HN═)C—; A is abenzene ring optionally substituted with up to 3 substituents orpyridine ring optionally substituted with up to 3 substituents, whereinsaid substituents selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy,C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino, cyano,HO—C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,acetyl, R³N(R⁴)C(═O)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, R³C(═O)N(R⁴)— and NH₂(HN═)C—; B isC₂₋₆ alkylene, C₃₋₇ cycloalkylene, C₂₋₆ alkenylene, or C₂₋₆ alkynyleneoptionally substituted with C₁₋₃ alkyl; W is NH or O; P is H, aprotecting group, or Z—S(O)₂—N(R²)—C(═O)—; Z is a 5-12 memberedmonocyclic or bicyclic aromatic ring optionally containing up to 3heteroatoms selected from O, N and S, wherein said 5-12 memberedmonocyclic or bicyclic aromatic ring is optionally substituted withhalo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄alkynyl, hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, nitro, amino, mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,C₁₋₄alkylC(═O)—, R³C(═O)N(R⁴)—, HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄alkylsulfonylamino, C₃₋₇ cycloalkyl, NH₂(HN═)C—, Q²—S(O)m-, Q²—O—,Q²—N(R³)— or Q²—; L is halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl,hydroxy, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,nitro, amino, mono- or di-(C₁₋₄ alkyl)amino, cyano, HO—C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, C₁₋₄alkylC(═O)—,HO(O═)C—, C₁₋₄alkyl-O(O═)C—, C₁₋₄ alkylsulfonylamino, C₃₋₇ cycloalkyl,R³C(═O)N(R⁴)—, NH₂(HN═)C—, R³N(R⁴)C(═O)— or R³N(R⁴)S(O)m-, or twoadjacent L groups are optionally joined together to form an alkylenechain having 3 or 4 members in which one or two (non-adjacent) carbonatoms are optionally replaced by oxygen atoms; m is 0, 1 or 2; and R²,R³, and R⁴ are independently selected from H and C₁₋₄ alkyl.